Charcot–Marie–Tooth disease and intracellular traffic

Progress in Neurobiology xxx (2012) xxx–xxx

G Model

PRONEU-1199; No. of Pages 35

Charcot–Marie–Tooth disease and intracellular traffic

Cecilia Bucci a,*, Oddmund Bakke b, Cinzia Progida b

a Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Monteroni, 73100 Lecce, Italyb Centre for Immune Regulation, Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2. Membrane traffic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.1. Steps of membrane trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2. The membrane traffic machinery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.1. Vesicle biogenesis: role of coats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.2. Vesicle biogenesis: role of dynamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.3. Vesicle biogenesis: role of phosphoinositides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.4. Vesicle motility: role of cytoskeletal proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.5. Vesicle tethering, docking and fusion: role of tethers and SNAREs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.2.6. Rab proteins and membrane traffic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.3. The ubiquitin/proteasome system in membrane trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.4. Mitochondrial dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

2.5. Membrane traffic in neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

A R T I C L E I N F O

Article history:

Received 4 June 2011

Received in revised form 23 December 2011

Accepted 13 March 2012

Available online xxx

Keywords:

Charcot–Marie–Tooth disease

Intracellular traffic

Membrane traffic

Peripheral neuropathy

Neurodegeneration

Polyneuropathy

Axon degeneration

A B S T R A C T

Mutations of genes whose primary function is the regulation of membrane traffic are increasingly being

identified as the underlying causes of various important human disorders. Intriguingly, mutations in

ubiquitously expressed membrane traffic genes often lead to cell type- or organ-specific disorders. This

is particularly true for neuronal diseases, identifying the nervous system as the most sensitive tissue to

alterations of membrane traffic. Charcot–Marie–Tooth (CMT) disease is one of the most common

inherited peripheral neuropathies. It is also known as hereditary motor and sensory neuropathy (HMSN),

which comprises a group of disorders specifically affecting peripheral nerves. This peripheral

neuropathy, highly heterogeneous both clinically and genetically, is characterized by a slowly

progressive degeneration of the muscle of the foot, lower leg, hand and forearm, accompanied by sensory

loss in the toes, fingers and limbs. More than 30 genes have been identified as targets of mutations that

cause CMT neuropathy. A number of these genes encode proteins directly or indirectly involved in the

regulation of intracellular traffic. Indeed, the list of genes linked to CMT disease includes genes important

for vesicle formation, phosphoinositide metabolism, lysosomal degradation, mitochondrial fission and

fusion, and also genes encoding endosomal and cytoskeletal proteins. This review focuses on the link

between intracellular transport and CMT disease, highlighting the molecular mechanisms that underlie

the different forms of this peripheral neuropathy and discussing the pathophysiological impact of

membrane transport genetic defects as well as possible future ways to counteract these defects.

� 2012 Elsevier Ltd. All rights reserved.

Abbreviations: CMT, Charcot-Marie-Tooth; DENN, differentially expressed in neoplastic versus normal cells; DNM2, dynamin 2; FYVE, Fab1p–YOTB–Vac1p–EEA1; GDAP1,

ganglioside induced differentiation associated protein-1; GEF, guanine nucleotide exchange factor; HMSN, hereditary motor and sensory neuropathy; HSPs, heat shock

proteins; KIF1b, kinesin family member 1b; LITAF, lipopolysaccharide-induced TNF factor; LRSAM1, leucine repeat and sterile alpha motif containing 1; MFN2, mitofusin 2;

MTMRs, myotubularin-related proteins; MVBs, multivesicular bodies; NDRG1, N-myc downstream regulated gene 1; Nedd4, neuronal precursor cell expressed

Contents lists available at SciVerse ScienceDirect

Progress in Neurobiology

jo u rn al ho m epag e: ww w.els evier . c om / lo cat e/pn eu ro b io

developmentally downregulated 4; NEFL, neurofilament light polypetide; OPA, optic atrophy proteins; PH, pleckstrin homology; PMP22, peripheral myelin protein 22;

PtdIns, phosphatidylinositol; PIs, phosphoinositides; SH3TC2, SH3 domain and tetratricopeptide repeats-containing protein 2; SIMPLE, small integral membrane protein of

lysosome/late endosome; SNAREs, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; Tsg101, tumor susceptibility gene 101.

* Corresponding author. Tel.: +39 0832 298900; fax: +39 0832 298626.

E-mail address: [email protected] (C. Bucci).

Please cite this article in press as: Bucci, C., et al., Charcot–Marie–Tooth disease and intracellular traffic. Prog. Neurobiol. (2012),doi:10.1016/j.pneurobio.2012.03.003

0301-0082/$ – see front matter � 2012 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pneurobio.2012.03.003

http://dx.doi.org/10.1016/j.pneurobio.2012.03.003

mailto:[email protected]


http://www.sciencedirect.com/science/journal/03010082


C. Bucci et al. / Progress in Neurobiology xxx (2012) xxx–xxx2

G Model


3. CMT disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.1. Clinical features of CMT disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.2. Classification of the different forms of CMT disease: axonal versus demyelinating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4. Genetic causes of CMT disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.1. Defects in vesicle budding: DNM2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.2. Defects in PI metabolism: MTMRs and FIG4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.2.1. MTMRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.2.2. FIG4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.3. Defects in cytoskeletal transport: KIF1B, NEFL and FGD4/Frabin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.3.1. KIF1B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.3.2. NEFL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.3.3. FGD4/Frabin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.4. Defects in the regulation of membrane traffic events: Rab7, NDRG1 and SH3TC2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.4.1. Rab7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.4.2. NDRG1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.4.3. SH3TC2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.5. Defects in the regulation of protein degradation: HSPs, LRSAM1 and LITAF/SIMPLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.5.1. HSPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.5.2. LRSAM1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.5.3. LITAF/SIMPLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.6. Defects in mitochondrial dynamics and mitochondrial axonal transport: MFN2 and GDAP1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.6.1. MFN2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.6.2. GDAP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.7. Defects in myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.8. Other defects: PRPS1 and ARHGEF10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.8.1. PRPS1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.8.2. ARHGEF10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9. Defects not directly related to trafficking: aminoacyl-tRNA synthetases, LMNA, BSCL2, TRPV4, CTDP1 and HK1 . . . . . . . . . . . . . . . . 000

4.9.1. Aminoacyl-tRNA synthetases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9.2. LMNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9.3. BSCL2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9.4. TRPV4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9.5. CTDP1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

4.9.6. HK1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

5. Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction

Compartmentalization is an essential feature of eukaryotic cellsand intracellular trafficking is the process responsible for thetransport of material between organelles. Indeed, membranetraffic comprehends a complex network of pathways connectingdifferent kinds of organelles and mediating the exchange ofcomponents between them. Membrane traffic presents two mainroutes, the biosynthetic (or exocytic) and the endocytic route, andit is fundamental for the development and the homeostasis of allmammalian tissues. Thus, alterations of intracellular traffic oftenresult in the development of diseases and in the last decade anumber of disorders have been linked to genetic defects inintracellular transport (Olkkonen and Ikonen, 2000, 2006).

Regarding the numerous membrane traffic disorders identifiedto date, the genetic defects affect components of the machinery forcargo sorting and biogenesis of vesicles, components of thecytoskeletal machinery for motility of transport vesicles, orcomponents of the machinery for tethering, docking and fusionof vesicles with their targets (Olkkonen and Ikonen, 2000, 2006). Asalterations of membrane traffic events have important conse-quences on different key cellular processes such as signaltransduction, proliferation, migration, apoptosis and mitosis, itis not surprising that mutations in membrane traffic genes oftengive rise to severe human disorders. In this respect, it is interestingto note that these diseases frequently affect the nervous system,possibly because this is a tissue highly sensitive to any kind ofinterference (Olkkonen and Ikonen, 2000, 2006; Tarabeux et al.,2010; Wang and Brown, 2010). Also, the morphology of neuronal

Please cite this article in press as: Bucci, C., et al., Charcot–Marie–doi:10.1016/j.pneurobio.2012.03.003

cells, bearing long axons and thus requiring an extremely efficientand organized intracellular vesicular trafficking to transportmaterial meters away from the cell body, could explain thissensitivity (Olkkonen and Ikonen, 2000, 2006).

It is now clear that a number of neuronal disorders are due tointracellular traffic defects or, at least, that alterations ofmembrane traffic are an important causative component (Morfiniet al., 2009; Salinas et al., 2008; Schweitzer et al., 2009). This is notsurprising if we consider that a number of neuronal processes, forinstance axon growth, repair and regeneration, heavily depend onmembrane traffic and, in particular, on iterative events ofendocytosis and exocytosis (Bloom and Morgan, 2011). In thisrespect, it is worth noting that in a number of membrane trafficdiseases, mutations actually affect ubiquitously expressed genesbut the defect is restricted to specific cell types, for instancecertain kinds of neurons (Chen et al., 2004b; Olkkonen and Ikonen,2000, 2006). With regard to neurons, this may be explained by agreater sensitivity of neuronal cells to the altered function of themutated protein due to their specific morphological character-istics, by the existence of specific membrane traffic pathways thatwould be affected, or by the existence of neuronal-specificinteractors of the mutated protein whose function would beimpaired.

In this review, we focus on the impact of intracellular trafficalterations on the insurgence of the most common hereditaryperipheral neuropathy, Charcot–Marie–Tooth (CMT) disease. Wediscuss recent research regarding the cellular and molecularmechanisms underlying the different forms of the neuropathy dueto alterations of intracellular traffic.

Tooth disease and intracellular traffic. Prog. Neurobiol. (2012),


C. Bucci et al. / Progress in Neurobiology xxx (2012) xxx–xxx 3

G Model


2. Membrane traffic

2.1. Steps of membrane trafficking

Intracellular membrane trafficking is the cellular processresponsible for the transport of material between different cellularorganelles. This process, which has to ensure efficiency, direction-ality, specificity and fidelity, is extremely complex and highlyregulated. During the last two decades, much effort was directedtowards uncovering the molecular mechanisms underlying thedifferent steps of membrane trafficking and several advances weremade allowing the identification of many components of themolecular machinery. Thus, many of the molecular mechanismsfor the maintenance of organelle identity and for the transport ofmaterial between organelles are now known. For each transportevent, there are at least five steps: formation of the vesicle andcargo sorting, vesicle motility, tethering of the vesicle to the targetcompartment, vesicle uncoating, docking and fusion of the vesiclewith the target compartment (Fig. 1). The process starts with theformation of a vesicle from the donor compartment. The buddingof the vesicle is mediated by a protein coat, which is responsible forshaping of the membrane and for cargo sorting. Having selected forthe cargo, which also comprises proteins of the membrane trafficmachinery important for the subsequent steps of transport, thevesicle pinches off the membrane. After pinching off, the vesiclemoves towards the target membrane and, eventually, physicallylinks itself (tethers), although loosely, to the target compartmentand loses its coat. The vesicle then docks and fuses with the targetcompartment, unloading into the target compartment its solubleand membrane-bound cargo (Fig. 1).

2.2. The membrane traffic machinery

The membrane traffic machinery is extremely complex andthere are various molecules responsible for the regulation of the

Fig. 1. Membrane traffic steps in a transport event. In order to achieve transport of memb

from the donor compartment selecting, with its coat, the cargo. Pinching off the mem

cytoskeletal tracks, the vesicle is then transported to the proximity of the target compart

SNAREs and t-SNAREs, docks and fuses to the target compartment, unloading its mem


different transport steps. We describe here the main componentsof the membrane traffic machinery, underscoring their role inmembrane traffic and their involvement in human diseases.

2.2.1. Vesicle biogenesis: role of coats

Fundamental for vesicle biogenesis and cargo selection is thevesicle’s coat (Bonifacino and Lippincott-Schwartz, 2003; Schek-man and Orci, 1996). The coat is composed by proteins that coverthe cytoplasmic side of a membrane segment, from which thevesicle will originate. Distinct coat proteins mediate differentbudding events and the coat is important initially to shape thetransport vesicle as the addition of coats to membranes causeschanges in membrane curvature (Bonifacino and Lippincott-Schwartz, 2003; Schekman and Orci, 1996). In addition, the coatselects by direct or indirect interaction the cargo molecules. Themost studied coat protein is clathrin, which complexes withadaptins to form the clathrin coat (Bonifacino and Lippincott-Schwartz, 2003; Schekman and Orci, 1996). Adaptins bind totransmembrane proteins to select them to be part of the nascentvesicle and also bind to transmembrane receptors that select forsoluble ligands in the vesicle (Bonifacino and Lippincott-Schwartz,2003; Schekman and Orci, 1996). Indeed, the inner shell of the coatis formed by different adaptins that interact to form the adaptorcomplex, which, in turn, interacts with membrane proteins thatcan then also select for the soluble cargo of the vesicle. Thus, themembrane of the vesicle is highly enriched with membraneproteins selected by the adaptor complex while the lumen isenriched with molecules sorted by membrane receptors bound tothe adaptor complex (Fig. 1). Apart from the clathrin coat, there area number of other vesicle coats in cells. It is worth mentioningcaveolins that bind to cholesterol and coat caveolae, flask-shapedinvaginations present in the plasma membrane of several cell types(Hansen and Nichols, 2010).

After pinching off the membrane, it was believed until recentlythat the coat is lost from the vesicle. However, data reported in the

rane-bound and soluble molecules from one compartment to another, a vesicle buds

brane is accomplished by dynamins or dynamin-related proteins. By moving on

ment and tethers to it. Following tethering, the vesicle, through the interaction of v-

brane and soluble content.



Fig. 2. Mechanisms of action of phosphatases involved in CMT neuropathy. FIG4 and

MTMRs are phosphatases responsible for the conversion of PIs, as shown in the

upper part of the figure. Phosphatidylinositol 3-phosphate (PtdIns3P) is present on

the early endosomal (EE) membrane and on the intraluminal vesicles of

multivesicular bodies (MVBs), whereas phosphatidylinositol 3,5-phosphate

(PtdIns(3,5)P2) is present on the limiting membrane of MVBs. The different

distribution of PIs is fundamental to determine and maintain membrane identity

and to guarantee the correct flux of material between the different endocytic

compartments.


G Model


last few years indicate that coat proteins and components of thetethering and docking machinery interact, strongly suggesting thatthe vesicle coat is maintained for a longer time period, and that itplays a role not only in vesicle biogenesis but also in thesubsequent steps of membrane trafficking (Cai et al., 2007b;Guo et al., 2008; Wassmer et al., 2009; Zink et al., 2009).

2.2.2. Vesicle biogenesis: role of dynamins

The vesicle pinch-off is regulated by dynamin, a large GTPase of100 kDa (Damke et al., 1994). The dynamin superfamily includes anumber of different families of proteins: the classic dynamins, suchas dynamin 1 (DNM1) and dynamin 2 (DNM2), the dynamin-likeproteins, the Mx proteins (GTPases with antiviral activity), theoptic atrophy proteins (OPA), the guanylate-binding proteins(GBP) and mitofusins (Haller and Kochs, 2002; Praefcke andMcMahon, 2004). These proteins function in various cellularprocesses, such as cytokinesis, division of organelles and buddingof vesicles, and share a common mechanism of action: dynaminrings are formed at the vesicle neck, then following GTP hydrolysis,membrane fission of vesicles from the parent membrane occurs.Membrane fission is often mediated by members of the dynaminsuperfamily, although each member participates in specifictransport steps. In particular, classic dynamins function in thebudding of clathrin-coated vesicles at the plasma membrane,cleavage furrow, Golgi, endosomes, caveolae and phagosomes.Dynamin-like proteins are involved in the division of organellessuch as mitochondria and peroxisomes. OPA1 and mitofusins areresponsible for the fusion of mitochondria (Chen et al., 2003;Legros et al., 2002; Praefcke and McMahon, 2004). There are alsoother fission events that are dynamin-independent and thatrequire the C-terminal-binding protein/brefeldinA-ADP ribosy-lated substrate (CtBP/BARS) (Bonazzi et al., 2005; Weigert et al.,1999). Alterations in members of the dynamin superfamily areresponsible for a number of human diseases and, in particular,cause a number of neuropathies (Reddy et al., 2011).

2.2.3. Vesicle biogenesis: role of phosphoinositides

Phosphoinositides (PIs) are important components of biologicalmembranes. They are phospholipids that derive from thephosphorylation of phosphatidylinositol (PtdIns). Differentialphosphorylation at different positions on the inositol ring leadsto the formation of different PIs, and each PI has a uniquelocalization in the cell. PI metabolism is finely regulated by kinasesand phosphatases, and they serve not only for the generation ofsecond messengers but also for membrane traffic, as they arespatio-temporal regulators specifying membrane identity (DeCamilli et al., 1996; Di Paolo and De Camilli, 2006; Liu andBankaitis, 2010). Indeed, local production of a single PI on amembrane represents the signal for the recruitment or theactivation of key membrane traffic proteins that will initiate, forinstance, vesicle formation (De Camilli et al., 1996; Di Paolo and DeCamilli, 2006).

PIs recruit and activate specific effector proteins, which containconserved PI-binding domains such as PH (pleckstrin homology),PX (phox homology), FYVE (Fab1p-YOTB-Vac1p-EEA1) and ENTH(epsin N-terminal homology) domains, to specific membranelocations (Balla, 2005).

In the classic PI turnover pathway, class III PI 3-kinase (vacuolarprotein sorting 34 (Vps34) in yeast) phosphorylates PtdIns intoPtdIns3P and type III PI 5-kinase (PIKfyve in mammals and Fab1p inyeast) phosphorylates PtdIns3P into PtdIns(3,5)P2 (Fig. 2). Reversereactions are catalyzed by the phosphatase FIG4 (Fig4p in yeast)which dephosphorylates PtdIns(3,5)P2 into PtdIns3P and by the 3-phosphatase myotubularins that dephosphorylate PtdIns(3,5)P2

into PtdIns5P and PtdIns3P into PtdIns (Nicot and Laporte, 2008)(Fig. 2).


PIs are also important regulators of cytoskeletal dynamics, celladhesion, cell motility and cytokinesis and thus they are involvedin several human disorders (Takenawa and Itoh, 2001). Inparticular, small changes in PI metabolism induce neurodegenera-tion, have detrimental effects on the nervous system and causedevelopmental disorders (Skwarek and Boulianne, 2009; Wenet al., 2011).

2.2.4. Vesicle motility: role of cytoskeletal proteins

Once the vesicle has been formed, it moves within the cytosol toreach the target or acceptor compartment. The movement is




G Model


mediated by the actin and tubulin cytoskeleton and, in particular,by cytoskeletal motor proteins that are able to move alongcytoskeletal tracks (myosins for actin filaments, kinesins anddyneins for microtubules) and are powered by the hydrolysis ofATP (DePina and Langford, 1999; Gill et al., 1991; Hehnly andStamnes, 2007; Holzbaur and Vallee, 1994; Sablin, 2000; Schroeret al., 1989; Urrutia et al., 1991). Indeed, the vesicle, through othercomponents of the molecular machinery, interacts with the correctmotor in order to be transported to its final destination.

The myosin superfamily includes 18 classes of motor proteinsthat move along actin filaments. They consist of a motor domain, aneck region and a tail region, and can be dimeric. They areimportant not only for intracellular membrane trafficking but alsofor muscle contraction, cytokinesis, cell migration and signaltransduction (Foth et al., 2006; Hirokawa et al., 2010).

The dynein superfamily includes cytoplasmic dyneins andaxonemal dyneins. Axonemal dyneins have a role in the bending ofcilia and flagella of eukaryotic cells (Mallik and Gross, 2004;Scholey, 2003). Cytoplasmic dyneins are homodimers consisting oftwo heavy chains (�520 kDa) with ATPase activity, two interme-diate chains (�74 kDa), four intermediate light chains (�33–59 kDa) and several light chains (�10–14 kDa) (Hirokawa et al.,2010; Karki and Holzbaur, 1999; Pfister et al., 2005). Cytoplasmicdyneins mediate the transport of different intracellular cargoes,such as mRNA, endosomes and viruses, as well as the transportwithin the flagellum and neurons (Aniento et al., 1993; Bremneret al., 2009; Levy and Holzbaur, 2006; Merino-Gracia et al., 2011;Pazour et al., 1999; Schnorrer et al., 2000).

The kinesin superfamily of motor proteins (KIF proteins) usesmicrotubules as ‘rails’ to transport cargoes. Kinesins consist of two120-kDa heavy chains and two 64-kDa light chains organized intwo globular heads, a stalk and a tail region. The globular domain(motor domain) has an ATP-binding domain that produces energyby hydrolyzing ATP for the movement along microtubules, and amicrotubule-binding site. The different KIFs share high sequencehomology in their motor domains, whereas the remaining parts ofthe molecules contain binding sites to different cargoes and areconsequently relatively divergent. Depending on its specificity, thevariable region may bind cargoes like mitochondria, lysosomes,endosomes, tubulin oligomers, intermediate filament proteins,mRNA complexes and other macromolecular complexes (Hiro-kawa et al., 2010; Hirokawa and Takemura, 2003). KIFs aretherefore important for a wide variety of intracellular transportsteps, including axonal and intraflagellar transport.

Microtubules are typically oriented with their ‘minus-ends’towards the nucleus and their ‘plus-ends’ towards the cellperiphery. Dynein motors mediate movements directed to themicrotubule minus-end, whereas most of the kinesins movetowards the plus-end (Hirokawa, 1998; Mallik and Gross, 2004).The microtubules in axons are lined up with their plus-endstowards the direction of the synapse. Axonal transport suppliesessential organelles and materials to nerve endings mainly byusing molecular motors like kinesins (Hirokawa et al., 2010;Hirokawa and Takemura, 2003).

Recently, the role of a third cytoskeletal component, theintermediate filaments, in membrane traffic has been investigated.Neurofilaments are the major intermediate filaments of neuronsand are composed of three subunits, heavy, medium and light,consisting of an N-terminal head, an a-helical central rod and a C-terminal tail domain (Liem, 1993). It has been established thatintermediate filaments have a key role not only in organellepositioning but also in organelle transport and function, indicatingthat they actually regulate intracellular vesicular traffic (Changet al., 2009; Styers et al., 2005, 2004).

Alterations of the cytoskeleton and, in particular, of cytoskeletalmotors cause a number of disorders and, in particular, are


responsible for the defective removal of intracellular aggregatesthat are a common cause of neurodegeneration (Ravikumar et al.,2005; Rubinsztein et al., 2005). Intermediate filament mutationsalso cause a number of disorders, and as they are expressed in atissue-specific manner, they are important in development anddifferentiation (Fuchs, 1994; Fuchs and Weber, 1994). In severalcases, intermediate filament disorders appear to be caused bydisruption of organelle positioning or signaling, as intermediatefilaments may also organize signal transduction (Eriksson et al.,2009). Given the recently discovered role of intermediate filamentsin membrane traffic (Chang et al., 2009; Minin and Moldaver,2008; Styers et al., 2005), the molecular mechanism underlying anumber of intermediate filament disorders could also be due to animpairment of their role in membrane traffic.

2.2.5. Vesicle tethering, docking and fusion: role of tethers and SNAREs

How does the vesicle recognize the target compartment? This isaccomplished with the help of tethering proteins and of SNAREs(soluble N-ethylmaleimide-sensitive factor attachment proteinreceptors) (Cai et al., 2007a; Pfeffer, 1999; Sollner, 2002; Sztul andLupashin, 2009).

Tethering is the initial attachment of the transport vesicle to thetarget compartment and precedes the interaction betweenSNAREs, present on vesicle and target membranes, that will leadto fusion. Tethering proteins or tethers are thus responsible for theinitial molecular recognition between the vesicle and the targetcompartment. There are different kinds of tethering molecules anddifferent tethers control the same intracellular vesicular trafficevent, suggesting that they could have different roles in promotingrecognition. Tethers can be long proteins with extensive coiled-coildomains and either dimers such as early endosomal antigen 1(EEA1) or multisubunit complexes such as HOPS and the exocyst(Brown and Pfeffer, 2010; Christoforidis et al., 1999; Hickey andWickner, 2010; Lipschutz et al., 2000; TerBush et al., 1996). Anumber of tethering proteins and tethering complexes have beenidentified and, importantly, it has been demonstrated that they areable to interact with components of the vesicle biogenesismachinery and of the fusion machinery. Indeed, it has beendemonstrated that tethers interact with components of the coat,with SNAREs and with Rab proteins, being Rab effectors and Rabexchange factors (Cai et al., 2007a; Pfeffer, 1999; Sollner, 2002;Sztul and Lupashin, 2009).

After the initial loose interaction through tethers, the vesicledocks to the target compartment. Docking is a much closerinteraction of the vesicle with the target membrane that ismediated by SNAREs present on the vesicle membrane (v-SNAREs)and SNAREs present on the target membrane (t-SNAREs) (Jahn andScheller, 2006). v-SNAREs and t-SNAREs interact and bring thevesicle in close contact with the target membrane, catalyzingvesicle fusion with the help of N-ethylmaleimide-sensitive factorand of soluble NSF attachment proteins (SNAPs) (Wickner, 2010).

The dysfunction of tethers and SNAREs is involved in a numberof disorders. For example, a SNARE protein redistribution has beenreported in a mouse model of Parkinson’s disease (Garcia-Reitbocket al., 2010) and a mutation in a SNARE protein, SNAP29, causes aneurocutaneous syndrome (Gissen et al., 2004; Sprecher et al.,2005).

2.2.6. Rab proteins and membrane traffic

Rab proteins are small GTPases important for the regulation ofmembrane traffic. The Rab family in human cells includes morethan 60 different members involved in the regulation of all the keysteps of intracellular vesicular trafficking. Indeed, Rab proteinscontrol formation, budding, uncoating, motility, tethering, dockingand fusion of vesicles, thus being coordinators of membrane traffic(Hutagalung and Novick, 2011; Stenmark, 2009). Rab proteins’




G Model


functions profoundly affect cell proliferation, cell nutrition, innateimmune response, mitosis and apoptosis. The action of Rabproteins in all these cellular processes is possible through theinteraction with multiple effector proteins such as molecularmotors, sorting adaptors, kinases, phosphatases or tethering andfusion factors (Hutagalung and Novick, 2011; Stenmark, 2009). RabGTPases cycle between an active GTP-bound, membrane-associat-ed form and an inactive GDP-bound form which is mostly cytosolic.After translation, the GDP-bound Rab protein interacts with Rabescort protein (REP), which presents the protein to geranylgeranyltransferase (GGT), thus adding a geranylgeranyl group to the twoC-terminal cysteines. This post-translational modification allowsmembrane anchoring of Rab protein. Then, on membranes, aguanine nucleotide exchange factor (GEF) stimulates Rab nucleo-tide exchange, causing Rab activation (Hutagalung and Novick,2011; Stenmark, 2009). The activated GTP-bound Rab then recruitsseveral effectors, and since any given Rab interacts with andregulates the function of different membrane traffic machinerycomponents, it contributes to many, if not all, aspects ofintracellular trafficking (Bucci and Chiariello, 2006; Grosshanset al., 2006; Hutagalung and Novick, 2011; Markgraf et al., 2007;Stenmark, 2009). Then, a GTPase-activating protein (GAP) inducesRab to hydrolyze GTP and to return to the inactive GDP-boundstate. Rab in the GDP-bound state is recognized by the GDPdissociation inhibitor (GDI), which removes Rab from themembrane (Hutagalung and Novick, 2011; Stenmark, 2009).

The Rab cycle is finely regulated and it is fundamental for theproper functioning of Rab protein and, thus, for correct regulationof membrane traffic events. Any kind of interference or perturba-tion of the cycle alters the regulation of intracellular trafficking andmay lead to diseases. Indeed, a number of disorders have beenlinked to Rab proteins and to their regulators. For example,choroideremia is caused by mutations in REP-1, X-linkednonspecific mental retardation is caused by mutations in GDI,Warburg Micro and Martsolf syndromes are caused by mutationsin Rab3GAP and nonsyndromic autosomal recessive mentalretardation is caused by mutations in TRAPPC9, a GEF for Rab1(Aligianis et al., 2005, 2006; D’Adamo et al., 1998; Mir et al., 2009;Mochida et al., 2009; Seabra et al., 1993). Rab proteins have beenimplicated in many genetic and acquired disorders (such asinfectious diseases and cancer) (Hutagalung and Novick, 2011;Mitra et al., 2011; Seabra et al., 2002). Interestingly, recent dataindicate that dysfunction of Rab proteins is a cause of neurologicaldiseases. For instance, Rab7 is mutated in CMT2B and Rab23 ismutated in Carpenter syndrome (Jenkins et al., 2007). Rab proteinsare also implicated in Parkinson’s and Huntington’s disease (Dalfoet al., 2004; Gitler et al., 2008), and mutations in huntingtin proteininhibit trafficking from the trans-Golgi network (TGN) to lateendosomes by interfering with Rab8 and its effector proteinoptineurin. In addition, huntingtin is important for nucleotideexchange and activation of Rab11, thereby impairing Rab11-regulated membrane trafficking and leading to oxidative stress andcell death (del Toro et al., 2009; Hattula and Peranen, 2000; Li et al.,2008, 2010).

2.3. The ubiquitin/proteasome system in membrane trafficking

Misfolded or abnormal proteins are normally recognized bychaperone molecules that refold them correctly. Heat shockproteins (HSPs) are molecular chaperones that prevent theformation of protein aggregates and assist proteins in theacquisition of their native structures. The name ‘heat shockprotein’ refers to their increased expression in response to elevatedtemperatures, although other stressful conditions are also capableof inducing their expression. HSPs can be classified into twogroups: the high molecular weight HSPs and the small HSP


superfamily. The human genome encodes 10 different small HSPs(HSPB1–HSPB10). Members of this superfamily are characterizedby low molecular mass (between 12 and 43 kDa), an a-crystallindomain consisting of 80–100 amino acids in the C-terminal region,and variable N- and C-terminal ends (Kappe et al., 2003; Koga et al.,2011). Small HSPs associate into oligomers and have a chaperone-like activity, interacting with partially denatured proteins andpreventing protein misfolding and aggregation (Dierick et al.,2005; Haslbeck et al., 2005; Stromer et al., 2003). They are alsoinvolved in other cellular activities such as modulation of actin andintermediate filament dynamics, apoptosis, cellular growth anddifferentiation (Arrigo, 2005; Gober et al., 2003; Gusev et al., 2002;Mehlen et al., 1997; Mounier and Arrigo, 2002). Given the role ofsmall HSPs in many cellular processes, it is not surprising that anumber of diseases, including neurodegenerative disorders, areconnected to mutations in these proteins (Dierick et al., 2005; Sunand MacRae, 2005).

However, when it is not possible to repair a damaged protein,chaperone molecules favor its degradation. Autophagy and theubiquitin/proteasome system are two different processes thatmediate the degradation of abnormal proteins (Koga et al., 2011).In chaperone-mediated autophagy, cytosolic proteins that need tobe degraded are recognized by a chaperone and targeted tolysosomes where the chaperone binds to a membrane receptor(Cuervo and Dice, 1996; Koga et al., 2011). In conditions such asacute oxidative stress and heat shock, or when the cell’s ability torefold or degrade abnormal polypeptides is exceeded, proteinsaggregate (Dubois et al., 1991; Johnston et al., 1998). Aggregatescan be degraded by autophagy, also referred to as aggrephagy(Yamamoto and Simonsen, 2011). Alterations of autophagy havebeen identified in many human neuropathies, for exampleParkinson’s, Alzheimer’s or Huntington’s disease (Cuervo et al.,2004; Wong and Cuervo, 2010).

In proteasome-mediated degradation, chaperone moleculesinteract with the ubiquitin/proteasome machinery, promoting thedegradation of aberrant proteins. The proteasome system, amulticatalytic ATP-dependent complex, recognizes and degradesproteins that have been tagged by a small molecule, ubiquitin. Theprocess of covalent attachment of ubiquitin to a substrate is knownas ubiquitination and it is mediated by three different enzymesthat work sequentially: an ubiquitin-activating enzyme E1, anubiquitin-conjugating enzyme E2 and an ubiquitin ligase E3(D’Azzo et al., 2005). As well as binding covalently to misfoldedcytoplasmic proteins and thereby priming them for proteasome-mediated proteolysis, ubiquitin also directs membrane proteins tothe endocytic pathway (Aguilar and Wendland, 2003; D’Azzo et al.,2005). The target protein can be ubiquitinated in various ways andthe type of ubiquitin linkages determine the protein’s fate.Ubiquitin can be attached to a single site (monoubiquitination)or to multiple sites on a substrate (multiubiquitination). Inaddition, ubiquitin contains seven lysine residues that can befurther ubiquitinated (polyubiquitination). Monoubiquitinationand K63-linkage are normally implicated in sorting and degrada-tion in the lysosome, whereas K48-, K11-linked chains and chainsof at least four ubiquitin molecules are usually a signal forproteasomal degradation (Aguilar and Wendland, 2003; Jin et al.,2008a; Raiborg and Stenmark, 2009; Thrower et al., 2000).Ubiquitination is a reversible modification and deubiquitinatingenzymes (DUBs) are responsible for the disassembling of poly-ubiquitin chains from the substrate before its degradation,recycling ubiquitin molecules and maintaining a pool of freeubiquitin in the cell (Lee et al., 2011a; Reyes-Turcu et al., 2009).Alterations in the ubiquitin/proteasome system lead to theaccumulation of protein inclusions in the cytosol and can causeneurodegenerative disorders (Bedford et al., 2008; Guthrie andKraemer, 2011).




G Model


2.4. Mitochondrial dynamics

Mitochondria are unique organelles bounded by a doublemembrane. They are responsible for many essential cellularfunctions, for example energy production, calcium homeostasis,cell growth, development and apoptosis. They form a dynamicnetwork whose proper distribution is important for cell survival.Their correct positioning is regulated by cytoskeletal elements, andlike transport vesicles, mitochondria move along cytoskeletaltracks. This movement occurs through the interaction withmolecular motors and adaptors that connect mitochondria tothe cytoskeleton: kinesins and cytoplasmic dyneins mediatetransport along microtubules, whereas myosins mediate transportalong actin filaments (Frederick and Shaw, 2007; Hollenbeck andSaxton, 2005). Milton is a kinesin-associated protein thatassociates with the adaptor Miro, a Rho GTPase localized on thecytosolic side of the mitochondrial outer membrane, to mediateanterograde mitochondrial transport (Fransson et al., 2006; Glateret al., 2006; Stowers et al., 2002). Syntabulin, an adaptor formicrotubule tracks that binds to the kinesin KIF5B, also promotesanterograde mitochondrial transport, while APLIP1, a kinesin-associated protein, promotes dynein-mediated retrograde move-ment (Cai et al., 2005; Horiuchi et al., 2005).

The transport and positioning of mitochondria in neurons arevery important due to the cell-specific morphology and to the largeamount of energy required at the synapses. Mitochondria aretransported from the cell body to synapses using kinesins to movealong microtubules (Frederick and Shaw, 2007; Tanaka et al.,2011). They can also move back to the cell body; however, themechanisms involved in this process remain to be fully character-ized (Zinsmaier et al., 2009). Disruption or alteration of theseprocesses causes various human neuropathies (Hollenbeck andSaxton, 2005).

Mitochondria also change their morphology through fusion anddivision. In physiological conditions, there is a balance betweenfusion and fission. Defects in this balance affect organellemorphology, distribution and mobility, often contributing to thedevelopment of neurodegenerative diseases (Bossy-Wetzel et al.,2003; Suen et al., 2008; Wang and Hong, 2002). The processes offusion and fission are not yet fully understood; however, they areknown to be regulated by mitofusins and dynamin-relatedproteins, members of the dynamin superfamily responsible forvesicle biogenesis. Mitofusins are transmembrane GTPases locatedin the mitochondrial outer membrane. There are two differentmitofusins in mammals: MFN1 and MFN2. They have a conservedGTPase domain in the N-terminal region, a bipartite transmem-brane domain, an internal HR1 (heptad repeat domain) region anda conserved a-helical region forming a coiled-coil structure (orHR2) at the C-terminus. The transmembrane domain of mitofusinsanchors the proteins to the mitochondrial outer membrane,exposing both the N- and C-ending to the cytoplasm (Koshibaet al., 2004; Rojo et al., 2002; Santel, 2006). The C-terminal coiled-coil domain of mitofusins is responsible for self-interaction of themolecules, allowing the formation of homo- and heterotypicoligomeric complexes. This interaction tethers adjacent mitochon-dria, initiating the fusion process that requires GTP hydrolysis(Koshiba et al., 2004). Another mitochondrial protein with adynamin-related GTPase domain involved in the fusion process isOPA1. OPA1 resides in the intermembrane space and it is anchoredto the inner mitochondrial membrane (Olichon et al., 2002). Sincemitochondria are double membrane organelles, four membraneshave to fuse during the fusion process: mitofusins mediate thefusion of the outer membranes, whereas OPA1 mediates the fusionof the inner membranes (Westermann, 2010). In the fissionprocess, the outer membrane protein FIS1 recruits DRP1 (dyna-min-related protein 1) from the cytosol. DRP1 contains a GTPase


domain that hydrolyzes GTP, inducing membrane constriction andscission, probably by a similar mechanism to the one utilized bydynamin to pinch off vesicles (James et al., 2003; Smirnova et al.,2001).

It is well established that close relationships exist betweenmitochondria and other cellular organelles. For instance, theendoplasmic reticulum (ER) and mitochondria closely communi-cate in order to regulate a number of physiological processes suchas mitochondrial energy production, lipid metabolism, apoptosisand calcium signaling. The interaction between the ER andmitochondria is mediated by mitofusins and is important forautophagosome biogenesis, since it provides membranes for theformation of this organelle during starvation (Hailey et al., 2010).In addition, there is an abundance of evidence demonstrating thatthe machinery responsible for the regulation of mitochondrialdynamics has several common components with the machineriesresponsible for intracellular vesicular trafficking. A Rab protein,Rab32, is localized to mitochondria and regulates mitochondria-associated membranes modulating apoptosis (Alto et al., 2002; Buiet al., 2010; Guan et al., 1993; Pitts et al., 1999). Rab32 is alsoimportant for the correct positioning of mitochondria in the cell(Alto et al., 2002; Bui et al., 2010).

Given the importance of mitochondrial dynamics, aberrantmitochondrial fusion, fission, movement and autophagy have beendetected in a number of neurodegenerative disorders such asParkinson’s, Alzheimer’s and Huntington’s disease (Chen and Chan,2009; Shirendeb et al., 2011, 2012). In addition, defects inmitochondrial axonal transport have been detected in a Drosophila

model of Friedreich’s ataxia and in amyotrophic lateral sclerosis(ALS) (De Vos et al., 2007; Shi et al., 2010; Shidara and Hollenbeck,2010).

2.5. Membrane traffic in neurons

In neurons, membrane trafficking and cargo delivery areessential for the growth, remodeling and maintenance of neurites,as well as for the proper functioning of synapses. Establishmentand maintenance of neuronal polarity are ensured by thecytoskeleton and membrane trafficking machinery (Foletti et al.,1999; Horton and Ehlers, 2003). As mentioned in Section 2.2.4, thecytoskeleton and molecular motors are indispensable in drivingthe movement of intracellular components along neurites in bothdirections: from and towards the cell body. Post-Golgi vesicles,recycling endosomes, late endosomes and lysosomes contribute tomembrane addition and protein/receptor trafficking.

The surface area and cytoplasmic volume of neurons are 10,000times greater than most eukaryotic cells and the length of axonscan be more than one meter (Horton and Ehlers, 2003). Most of theproteins that are necessary for the maintenance and function of theaxon and synaptic terminal after their synthesis in the cell bodyneed to be transported along the axon. Energy, organelles andcargo molecules also need to travel a long distance to reach theaxonal tip. At the axon terminal, synaptic vesicles containingneurotransmitters are exocytosed and endocytosed after releasingtheir content at cell–cell contact sites, the synapses. It is importantto point out that motor and sensory neurons have generally verylong axons that extend far out from the cell body and thus theyhave a greater need for energy, transport of organelles andmolecules as well as myelin.

Intracellular transport in neurons is also important in the processof myelination. Myelin is a multilayered membrane structuregenerated in the CNS by oligodendrocytes and in the peripheralnervous system by Schwann cells which extend spirals of membranearound the axon of neurons. Schwann cells myelinate only oneaxonal segment, whereas oligodendrocytes extend several process-es, myelinating various axons simultaneously (Nave, 2010). Myelin




G Model


is not continuous along axons and in the discontinuous sites, termednodes of Ranvier, the propagation of action potentials occurs. Thebiogenesis and maintenance of myelin require a tight control of theintracellular transport of myelin proteins and lipids (Anitei andPfeiffer, 2006; Baron and Hoekstra, 2010; Kramer et al., 2001).Following synthesis at the ER and transport to the Golgi apparatus,various trafficking routes appear to direct myelin components totheir final destination: direct transport from the TGN, indirect viaendosomes, or via transcytosis (Kramer et al., 2001; Maier et al.,2008). Myelin ensures fast saltatory conduction along vertebrateaxons and perturbations in myelin protein trafficking and/orturnover are associated with a number of neurological disorders(Kramer et al., 2001; Nave, 2010; Scherer and Wrabetz, 2008).

3. CMT disease

CMT disease is the most common hereditary peripheralneuropathy with a prevalence of 1:2500 (Skre, 1974). CMT disease,also classified as hereditary motor and sensory neuropathy(HMSN), is highly heterogeneous comprising a number ofgenetically distinct disorders that exhibit similar clinical symp-toms. CMT neuropathy was first described in 1886 by Jean MartinCharcot and his student Pierre Marie in France, and by HowardHenry Tooth in Cambridge. CMT disease affects both motor andsensory nerves. Following the first identification of a duplication ofthe peripheral myelin protein 22 (PMP22) gene as the cause of oneform of CMT disease, CMT1A (Lupski et al., 1991; Raeymaekerset al., 1991), several other genetic causes of CMT neuropathy havebeen discovered. More than 30 CMT disease-causative genes arenow known, allowing accurate genetic diagnosis in about 70% ofpatients (Table 1) (Banchs et al., 2009; Berciano, 2011; Pareysonand Marchesi, 2009; Reilly et al., 2011). Although some clinicaltrials are in progress, no specific treatment for CMT diseasecurrently exists and rehabilitative strategies are presently the mosthelpful therapies to patients (Schenone et al., 2011). A recent trialon the use of ascorbic acid in patients affected by CMT1A, based onevidence that in transgenic mice the severity of the neuropathy isreduced by this treatment, unfortunately showed no significanteffect in humans (Pareyson et al., 2011; Passage et al., 2004).

3.1. Clinical features of CMT disease

The age of onset of CMT disease is within the first or seconddecade of life (although it has been reported to be as late as theseventh decade), with no race predilection. Lifespan is not affected,although CMT neuropathy is characterized by slowly progressiveweakness of the distal muscles that can lead to muscle atrophy(Barisic et al., 2008; Pareyson et al., 2006; Skre, 1974). The weaknessusually starts in the legs and feet, then subsequently affects handsand arms. Patients first experience difficulties in walking as thedisorder affects lower leg muscles first. If foot muscles are heavilyaffected, this also leads to foot deformities such as ‘pes cavus’ withhigh arches and hammertoes (where the middle joint of a toe bendsupwards) (Barisic et al., 2008; Pareyson et al., 2006; Skre, 1974).Other features are decreased or absent tendon reflexes, the inabilityto hold the foot horizontal (foot drop) and a high-stepped gait withfrequent tripping and falls. If the weakness also affects the hands andarms, this results in hand deformities with poor finger control andincreasing difficulties in writing and manipulating small objects(Barisic et al., 2008; Pareyson et al., 2006; Skre, 1974). The differentextents of sensory loss that accompany the various forms of thedisorder are generally more serious distally, with numbness at thefeet or legs frequently recorded. Some forms of the disease aretermed ulcero-mutilating as they are characterized, in addition toprominent sensory loss, by frequent toe and foot ulcers, withrecurrent infections often leading to amputations (Barisic et al.,


2008; Pareyson et al., 2006; Skre, 1974). Thus, complications of CMTneuropathy are represented by progressive weakness, progressiveinability to walk and manipulate objects, and frequent injuries inareas of the body displaying decreased sensation. Other associatedclinical symptoms are deafness, hand tremors, diaphragm palsy,vocal cord palsy, pyramidal signs, papillary abnormalities, opticalnerve atrophy, mental retardation and renal failure (Barisic et al.,2008; Patzko and Shy, 2011; Schenone et al., 2011).

3.2. Classification of the different forms of CMT disease: axonal versus

demyelinating

CMT disease includes several clinically and genetically distinctdisorders that have been classified mostly according to nerveconduction velocities. In 1968, Dyck and Lambert started toclassify neuronal peripheral disorders as HMSN and divided theminto two groups: type 1 with low nerve conduction velocities andtype 2 with normal or near-normal nerve conduction velocities(Dyck and Lambert, 1968). In 1980, Harding and Thomas, studying228 HMSN patients, noted that nerve conduction velocitiesexhibited a bimodal distribution and thus decided to set athreshold of 38 m/s to separate patients into the two categories(Harding and Thomas, 1980). Thus, on the basis of electrophysio-logical properties and neuropathology, CMT neuropathy has beendivided into two main types: CMT1 (or HMSN type I) with nerveconduction velocities below 38 m/s, caused by abnormalities inthe myelin sheath and called demyelinating, and CMT2 (or HMSNtype II) with nerve conduction velocities greater than 38 m/s,caused by abnormalities in the axon and thus called axonal. Indemyelinating CMT forms, the defect generally affects Schwanncells first and, as a consequence, causes axonal loss. Indeed, in theperipheral nervous system, Schwann cells tightly communicatewith axons in order to regulate their development, function andmaintenance (Corfas et al., 2004). Failing of this interaction due todamaged Schwann cells results in axonal damage and degenera-tion (as in demyelinating CMT) and axonal neurofilamentsbecome more dense; it has been proposed that denser packingof neurofilament is the cause of axonal injury although this has notbeen proved yet (de Waegh and Brady, 1990; de Waegh et al.,1992). In axonal CMT forms, it is axonal transport that is affected,subsequently causing degeneration of the axon. Biopsies of suralnerves from patients affected by demyelinating CMT forms showsegmental demyelination, whereas the same type of biopsies frompatients with the axonal form present axonal loss but notdemyelination (Szigeti and Lupski, 2009). However sometimesthe electrophysiological distinction between demyelinating andaxonal forms may be difficult. Indeed in the neuropathies withprimary involvement of myelin or Schwann cells, secondaryaxonal degeneration can occur, while in primarily axonalneuropathies, secondary demyelination may also be present(Hanemann and Gabreels-Festen, 2002; Krajewski et al., 2000;Tankisi et al., 2007). Although this classification is still used, thedifferent CMT forms are classified considering not only theelectrophysiological and anatomical findings, but also consider-ing inheritance genetic patterns and the causative mutant genes(Reilly, 2007; Reilly et al., 2011). Consequently, an increasednumber of CMT forms has been identified, including thedemyelinating autosomal dominant CMT1 (AD CMT1) form, thedemyelinating autosomal recessive CMT1 (AR CMT1 or CMT4)form, the axonal autosomal dominant CMT2 (AD CMT2) form, theaxonal autosomal recessive (AR CMT2) form and the X-linked(CMTX or CMT5) form. In addition, dominant intermediate (DI-CMT) forms of the disease with intermediate median motor nerveconduction velocities have also been described. A further divisionof each type into subtypes depends on the genetic defect (Table 1)(Reilly, 2007; Reilly et al., 2011).



Table 1Genetic defects associated with the different clinical forms of CMT disease and the proposed pathogenetic mechanisms.

Type Gene/locus Gene function Disease mechanism

Demyelinating autosomal dominant – AD CMT1

CMT1A PMP22 Myelination Duplication/gene dosage/altered myelination

CMT1B MPZ Myelination PM/altered myelination

CMT1C LITAF/SIMPLE Protein degradation PM/altered protein degradation?

CMT1D EGR2 Transcription of genes involved in myelination PM/altered myelination

CMT1E PMP22 Myelination PM/altered myelination

CMT1F NEFL Cytoskeleton PM/defective transport and assembly of

neurofilaments/delayed neuroregeneration

HNPP PMP22 Myelination Deletion/gene dosage/altered myelination

Demyelinating autosomal recessive – AR CMT1 or CMT4

CMT4A GDAP1 Mitochondrial dynamics PM/altered mitochondrial distribution in axons

CMT4B1 MTMR2 Dephosphorylation of PIs PM/reduced phosphatase activity/altered membrane

recycling in neurons

CMT4B2 MTMR13 Dephosphorylation of PIs PM/reduced phosphatase activity/altered membrane

recycling in neurons

CMT4C SH3TC2 Membrane traffic PM/altered recycling in neurons

CMT4D NDRG1 Membrane traffic PM/altered membrane traffic

CMT4E EGR2 Transcription of genes involved in myelination PM/altered myelination

CMT4F PRX Maintenance of peripheral nerve myelin PM/altered myelination/altered ensheathing of

regenerating axons

CMT4G HK1 Energy production PM/alteration of cell survival?

CMT4H FGD4 (Frabin) Regulation of actin cytoskeleton PM/abnormal cytoskeletal transport?/altered PI metabolism?

CMT4J FIG4/SAC3 Dephosphorylation of PIs PM/altered PI metabolism

CCFDN CTDP1/FCP1 Dephosphorylation of RNA polymerase II PM/aberrant splicing/altered transcription of myelin genes?

AR CMT1 PMP22 Myelination PM/altered myelination

AR CMT1 or DSN/CH MPZ Myelination PM/altered myelination

Axonal autosomal dominant – AD CMT2

CMT2A1 KIF1B Movement on microtubules PM/altered axonal transport

CMT2A2 MFN2 Mitochondrial dynamics PM/altered axonal mitochondrial transport and

mitochondrial dynamics

CMT2B RAB7A Regulation of membrane traffic PM/altered axonal transport

CMT2C TRPV4 Cation channel PM/changes in calcium concentration?

CMT2D GARS Protein translation PM/altered translation in the axons?

CMT2D or SS BSCL2/Seipin ER transmembrane protein? PM/ER stress?

CMT2E NEFL Cytoskeletal transport PM/defective transport and assembly of

neurofilaments/delayed regeneration

CMT2F HSPB1 Protein degradation PM/altered protein degradation

CMT2G 12q12-q13 (FGD4?) ? ?

CMT2I/J MPZ Myelination PM/altered myelination

CMT2H/K GDAP1 Mitochondrial dynamics PM/altered mitochondrial distribution in axons

CMT2L HSPB8 Protein degradation PM/altered protein degradation?

CMT2M AARS Protein translation PM/altered translation in the axons?

Axonal autosomal recessive – AR CMT2

CMT2B1 LMNA Nuclear architecture PM/decreased resistance to mechanical stress in neurons?

CMT2B2 MED25 Transcription PM/altered transcription of myelin genes?

AR CMT2 GDAP1 Mitochondrial dynamics PM/altered mitochondrial distribution in axons

AR CMT2 LRSAM1 Protein degradation PM/altered protein degradation?

Dominant intermediate – DI-CMT

DI-CMTA 10q24. 1-25.1 ? PM/?

DI-CMTB DNM2 Vesicle budding PM/alterations of membrane traffic?

DI-CMTC YARS Protein translation PM/altered translation in the axons?

Slow NCV ARHGEF10 Regulation of actin cytoskeleton PM/myelin defects during development

X-linked CMT or CMT5

CMTX1 GJB1 Gap junctions PM/impaired interactions between glia and

neurons/myelination defects

CMTX2 Xp22.2 ? ?

CMTX3 Xq26 ? ?

CMTX4 Xq24-q26.1 ? ?

CMTX5 PRPS1 Nucleotide biosynthesis PM/reduced nucleotide availability/myelination

or G-protein defects?

AARS, alanyl-tRNA synthetase; ARHGEF10, Rho guanine nucleotide exchange factor 10; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CCFDN, congenital cataracts

facial dysmorphism neuropathy; CH, congenital hypomyelination; CTDP1, C-terminal domain phosphatase 1; DNM2, dynamin 2; DSN, Dejerine–Sottas neuropathy; EGR2,

early growth response protein 2; FCP1, TFIIF-associating RNA polymerase C-terminal domain phosphatase 1; FGD4, FYVE, RhoGEF and PH domain-containing protein 4; GARS,

glycyl-tRNA synthetase; GDAP1, ganglioside-induced differentiation-associated protein 1; GJB1, Gap junction protein b1; HK1, hexokinase 1; HNPP, Hereditary Neuropathy

with liability to Pressure Palsies; HSPB1, heat shock protein beta-1; HSPB8, heat shock protein beta-8; KIF1B, kinesin family member 1b; LITAF, lipopolysaccharide-induced

TNF factor; LMNA, lamin A/C; LRSAM1, leucine rich repeat and sterile alpha motif 1; MED25, Mediator complex subunit 25; MFN2, mitofusin 2; MTMR, myotubularin-related

protein; MPZ, myelin protein zero; NCV, nerve conduction velocity; NDRG1, N-myc downstream regulated gene 1; NEFL, neurofilament light chain; PM, point mutation;

PMP22, peripheral myelin protein 22; PRPS1, phosphoribosylpyrophosphate synthetase 1; PRX, periaxin; SAC3, SAC domain containing protein 3; SH3TC2, SH3 domain and

tetratricopeptide repeats-containing protein 2; SIMPLE, small integral membrane protein of lysosome/late endosome; SS, Silver syndrome; TRPV4, transient receptor

potential cation channel subfamily V member 4; YARS, tyrosyl-tRNA synthetase; ?, unknown.


G Model


Please cite this article in press as: Bucci, C., et al., Charcot–Marie–Tooth disease and intracellular traffic. Prog. Neurobiol. (2012),doi:10.1016/j.pneurobio.2012.03.003



G Model


Mutated proteins in neurons are generally the cause of bothdominantly and recessively inherited forms of axonal CMT. Inthese cases, mutations have a cell-autonomous effect, i.e. mutantcells exhibit an altered phenotype independently of mutations inother cell types which interact with the affected neurons.Dominantly and recessively inherited forms of demyelinatingCMT are due to a cell-autonomous effect in Schwann cells, whereonly mutated proteins expressed in Schwann cells are responsiblefor the demyelination. However, the expression of the mutantproteins by other cell types in these cases can contribute to thealtered phenotype in peripheral neuropathies and CMT disease in anon-cell-autonomous manner (Suter and Scherer, 2003). In a non-cell-autonomous disorder, mutations affect cells in the proximityof the target neurons (such as glial cells, astrocytes, oligoden-drocytes and microglia), eventually leading the target cells toexhibit a mutant phenotype (Boillee et al., 2006; Custer et al., 2006;Di Giorgio et al., 2007; Nagai et al., 2007; Yazawa et al., 2005). Forexample, mutations in proteins expressed in glial cells can eithercause the release of toxic components or alter neuronal supportfunctions, leading to damages to the neighboring neurons(Lobsiger and Cleveland, 2007).

4. Genetic causes of CMT disease

Since the initial discovery of PMP22 as the causative gene forCMT1A (Matsunami et al., 1992; Patel et al., 1992; Timmermanet al., 1992; Valentijn et al., 1992), more than 30 genes have beenlinked to CMT neuropathy, and for several loci associated withdifferent forms of the disease, the identification of the responsiblegene is still in progress. In this review, we decided to group theidentified CMT disease-causative genes on the basis of theirfunction in order to obtain a clearer idea of the multiple processesthat, if altered, cause the disorder. Of course, the optimum way ofdoing this would be to classify the genes on the basis of the alteredfunction that gives rise to the disorder. However, as genes usuallyhave more than one function or influence more than one cellularprocess, and for many of the CMT disease-causative genes themolecular mechanism leading to the disorder is still not known,this was not always possible. Therefore, upon consideration of allthe proven functions of each gene, we have grouped the genesbased on the altered function most likely to be responsible to leadto the neuropathy. We believe that this classification is a usefulstarting point to fully understand the molecular causes of thedifferent forms of the disorder. We list all the genes, pathways andprocesses involved in the pathogenesis of CMT disease in order toprovide a comprehensive representation of all the genetic defectsinvolved. In the following sections, however, we focus on thealterations of membrane traffic genes and discuss in detail theirputative mechanisms of action.

4.1. Defects in vesicle budding: DNM2

DNM2 is a large GTPase which is ubiquitously expressed(Diatloff-Zito et al., 1995). It consists of a GTPase domain at the N-terminus, a middle domain (MD), a PH domain, a GTPase effectordomain (GED) and a proline-rich domain (PRD) at the C-terminus.The catalytic GTPase domain binds and hydrolyzes GTP in order todeform membranes; the MD binds to g-tubulin and is responsiblefor DNM2 self-assembly (Durieux et al., 2010; Thompson et al.,2004). The PH domain is involved in the interaction withmembrane PIs, especially phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2), targeting DNM2 to membranes (Klein et al., 1998;Zheng et al., 1996). The GED participates in the self-assembly ofDNM2 and acts as a GAP (Sever et al., 1999). The PRD is the bindingsite for proteins that interact with dynamin via Src-homology 3(SH3) domains (Dong et al., 2000; Soulet et al., 2005). DNM2 is


subjected to several post-translational modifications. It can bephosphorylated by Src kinase, leading to albumin endocytosis andmembrane vesiculation at the TGN, or dephosphorylated, leadingto dopamine-induced Na+K+-ATPase endocytosis (Efendiev et al.,2002; Shajahan et al., 2004; Weller et al., 2010). DNM2 canundergo S-nitrosylation by nitric oxide, with subsequent increaseof its GTPase activity and endocytosis (Kang-Decker et al., 2007).Finally, cathepsin L cleaves cytoplasmic DNM2 at positions 355–360 in the MD (Sever et al., 2007).

DNM2 is mainly involved in membrane trafficking and in theformation and release of vesicles from membranes (Fig. 1). Itparticipates in clathrin-dependent and clathrin-independentendocytosis, in intracellular trafficking from endosomes and theGolgi apparatus and regulates both the actin and tubulincytoskeleton not just in connection with membrane traffickingprocesses (Durieux et al., 2010). DNM2 co-localizes with clathrin-coated vesicles and plays a role during their maturation (Loerkeet al., 2009; Rappoport and Simon, 2003; Warnock et al., 1997). Itforms a complex with sorting nexin 9 (SNX9) and fructose-1,6-bisphosphate aldolase. Phosphorylation of SNX9 induces therelease of aldolase from the SNX9–DNM2 complex, recruitingDNM2 to the plasma membrane (Lundmark and Carlsson, 2004).DNM2 binds to PtdIns(4,5)P2 and proteins containing BAR domains(such as amphiphysins and SNX9) on the membrane and forms anoligomer helical structure around the neck of the nascent vesicles(Shin et al., 2008b; Warnock et al., 1997). Finally, SNX9 promotesdynamin GTPase activity, and GTP hydrolysis results in membraneconstriction and vesicle scission (Lundmark and Carlsson, 2005;Soulet et al., 2005). DNM2 is also involved in clathrin-independentendocytosis, like micropinocytosis and macropinocytosis, as wellas in the formation of phagosomes and caveolae (Cao et al., 2007;Gold et al., 1999; Henley et al., 1998; Liu et al., 2008; Predescu et al.,2003). In addition, DNM2 localizes to the TGN where it associateswith cortactin and syndapin 2 and regulates vesicle formation (Caoet al., 2005; Jones et al., 1998; Kessels et al., 2006; Kreitzer et al.,2000; Maier et al., 1996). Recent studies have also demonstrated aninvolvement of DNM2 in exocytosis, even though its role in theexocytic machinery is not clear (Arneson et al., 2008; Jaiswal et al.,2009; Min et al., 2007). DNM2 interacts with and is involved in theregulation of actin and microtubule networks. It interacts withAbp1 (actin-binding protein 1), a Src kinase that physically linksthe endocytosis machinery to the cortical actin network, andcortactin, a component of the cortical actin cytoskeleton thatregulates actin polymerization (Kessels et al., 2001; Mooren et al.,2009; Schafer et al., 2002). Interaction between DNM2 and theactin cytoskeleton is important not only for endocytosis andvesicle formation, but also for the formation of membrane tubulesand protrusions and for cell migration. Indeed DNM2, togetherwith cortactin and Arp2/3, reorganizes actin at the edge ofmigrating cells, allowing lamellipodia formation (Krueger et al.,2003). Additionally, it is present in other structures important forcell migration, such as cortical ruffles, podosomes and invadopo-dia, as well as in focal adhesions and actin-stress fibers(Baldassarre et al., 2003; Ezratty et al., 2005; McNiven et al.,2000; Ochoa et al., 2000; Schlunck et al., 2004; Yoo et al., 2005). ThePRD region of DNM2 interacts with microtubules, regulating theirpolymerization–depolymerization (Hamao et al., 2009; Lin et al.,1997; Tanabe and Takei, 2009; Warnock et al., 1997). Moreover,DNM2 binds to g-tubulin and it has been described as a componentof the centrosome (Thompson et al., 2004). It has also beenreported that DNM2 participates in all the phases of mitosis,suggesting a role in the regulation of many different microtubule-dependent processes (Liu et al., 2008; Thompson et al., 2002).Furthermore, DNM2 is capable of triggering apoptosis and theGTPase domain of DNM2 is important in this function (Fish et al.,2000; Soulet et al., 2006).




G Model


Four isoforms are expressed by the DNM2 gene using acombination of two alternative splice sites. Each DNM2 isoformappears to perform specific functions: data suggest that isoforms 1and 3 are preferentially involved in clathrin and caveolae-dependent endocytosis, whereas isoforms 2 and 4 are preferen-tially involved in uncoated endocytosis and trafficking from theGolgi (Durieux et al., 2010; Liu et al., 2008). The DNM2 gene hasrecently been described as a susceptibility gene for late-onsetAlzheimer’s disease (Aidaralieva et al., 2008). Furthermore,mutations in the DNM2 gene cause rare forms of DI-CMT type B(DI-CMTB) peripheral neuropathy and autosomal dominantcentronuclear myopathy (CNM) (Bitoun et al., 2005, 2008; Fabriziet al., 2007b; Gallardo et al., 2008; Zuchner et al., 2005). In DI-CMTB, five different DNM2 mutations have been identified in theN-terminal region of the PH domain and one in the MD (Bitounet al., 2008; Fabrizi et al., 2007b; Gallardo et al., 2008; Zuchneret al., 2005). Due to the ubiquitous expression of DNM2, DNM2mutations appear to affect both Schwann cells and neurons(Niemann et al., 2006).

To date, the mechanisms involved in the pathophysiology ofdisorders caused by DNM2 mutations are unknown, even thoughmany reports suggest that an impairment in membrane traffickingcontributes to the pathogenesis of DI-CMTB. Impairment ofclathrin-mediated endocytosis has been demonstrated in culturedcells expressing CNM or CMT-DNM2 mutants, and one of the DI-CMTB mutants was shown to alter the intracellular trafficking ofthe transferrin-containing compartment (Bitoun et al., 2009;Tanabe and Takei, 2009). In addition, DI-CMTB mutants candisorganize the microtubule cytoskeleton, and one of them hasbeen shown to impair microtubule-dependent membrane trans-port (Tanabe and Takei, 2009; Zuchner et al., 2005). This isconsistent with observations that suggest neuropathies, includingCMT neuropathy, are caused by defects in membrane transportsteps such as endocytosis, axonal transport, or protein degradation(Suter and Scherer, 2003). In DI-CMTB, DNM2 mutations that alterthe microtubule network may lead to abnormal axonal transportand protein trafficking, a pathophysiological mechanism previ-ously described in various forms of CMT disease. Interestingly,DNM2 has recently been found on late endosomes in a complexwith CIN85 and Rab7, and Rab7 mutations are also responsible fora form of CMT neuropathy (Schroeder et al., 2010; Verhoeven et al.,2003a).

The fact that DNM2 is involved in a wide variety of functionsand interacts with various proteins makes the identification of thepathogenetic mechanisms in DI-CMTB difficult. Additionally, thephenotype of DI-CMTB patients could be due to impairment of thevarious functions of the protein. How DNM2 mutations alter cellfunction in tissue-specific disorders is currently an important issuethat awaits to be resolved. However, it is interesting to note thatinhibition of DNM1 expression, as well as inhibition of expressionof its interacting partner amphiphysin 1, prevents neuriteformation in cultured hippocampal neurons, indicating thatDNM1 function is required for normal neuronal morphogenesis(Mundigl et al., 1998; Torre et al., 1994). Thus, the role of DNM2 inneurite outgrowth and neuritogenic signaling and the effects ofexpression of DNM2 mutant proteins causing CMT disease on theseprocesses should be investigated. The findings of such studiescould contribute to establishing the mechanism of CMT neuropa-thy.

4.2. Defects in PI metabolism: MTMRs and FIG4

4.2.1. MTMRs

Myotubularin-related proteins (MTMRs) are a family ofubiquitously expressed PI 3-phosphatases consisting of catalyti-cally active or inactive members in humans. Active MTMRs possess


3-phosphatase activity towards both PtdIns3P and PtdIns(3,5)P2

polyphosphoinositides, suggesting an involvement in intracellulartrafficking and membrane homeostasis (Fig. 2) (Robinson andDixon, 2006). PtdIns3P is produced by a class III PI 3-kinase inmammals, which corresponds to the Vps34 protein in yeast, and isimportant for endosome function. PtdIns3P is highly enriched onearly endosomes and on the internal vesicles of multivesicularbodies (MVBs), and is involved in membrane transport (Lindmoand Stenmark, 2006; Schu et al., 1993). It recruits effector proteinscontaining FYVE, PX or PH motifs such as EEA1 that cooperateswith the activated Rab5 GTPase to regulate early endosomal fusionand hepatocyte growth factor-regulated tyrosine kinase substrate(Hrs) that controls the first steps of receptor sorting andinternalization within the MVBs (Gillooly et al., 2000; Raiborget al., 2001; Roth, 2004; Simonsen et al., 1998). The other MTMRsubstrate, PtdIns(3,5)P2, is generated by the phosphorylation ofPtdIns3P by PIKfyve in mammals and by Fab1p in Saccharomyces

cerevisiae (Gary et al., 1998; Sbrissa et al., 1999). PIKfyve islocalized on early endosomes and regulates retrograde transport;however, PtdIns(3,5)P2 subcellular localization and function havenot been fully elucidated (Cabezas et al., 2006; De Lartigue et al.,2009; Ikonomov et al., 2003; Rutherford et al., 2006). PtdIns(3,5)P2

is present at a very low abundance in cells and it was originallydiscovered in yeast, where its levels increase in response tohyperosmotic shock, leading to a reduction in vacuole size (Doveet al., 1997). PtdIns(3,5)P2 is implicated in a number of cellularprocesses, including control of the size and acidification ofendosomes and lysosomes, regulation of retrograde membranetrafficking from lysosomes and late endosomes to the Golgicomplex and ubiquitin-dependent sorting of some cargo proteinsinto MVBs (Dove et al., 1997, 2004; Efe et al., 2005; Michell et al.,2006; Mollapour et al., 2006; Odorizzi et al., 1998; Rudge et al.,2004; Rusten et al., 2006; Shisheva, 2008). Since MTMR substratesfunction within the endosomal–lysosomal pathway, it is notsurprising that MTMRs themselves also play a role in endocytosisand trafficking of membranes and proteins (Naughtin et al., 2010;Tsujita et al., 2004).

Among the MTMRs, MTMR2 is a catalytically active phospha-tase of 643 amino acids with a PH-GRAM (pleckstrin homology,glucosyltransferase, Rab-like GTPase activator and myotubularin)domain, which binds PIs; a PTP (protein tyrosine phosphatase)domain; a coiled-coil domain for homo- and heterodimerizationwith other members of the family, such as MTMR13; and a PSD-95-Dlg-ZO-1-binding domain (PDZ-BD) at the C-terminus (Begleyet al., 2003; Robinson and Dixon, 2005). Many studies have shownthat MTMR2 localization is mainly cytosolic, with enrichment inthe perinuclear region (Berger et al., 2003; Franklin et al., 2011;Laporte et al., 2002; Previtali et al., 2003; Robinson and Dixon,2005). However, it has also been shown that both overexpressedand endogenous MTMR2 significantly co-localizes with the lateendocytic protein Rab7, and binds to the hVps34/hVps15 complex,suggesting that MTMR2 functions within the endocytic pathwayregulating PtdIns3P levels (Cao et al., 2008). Under certainconditions, such as changes in the levels of intracellular PIs,dephosphorylation and/or after interaction with an inactivepartner like MTMR5, MTMR2 localizes to precise subcellularcompartments (Kim et al., 2003). Indeed, unphosphorylatedMTMR2 localizes to endocytic compartments where it depho-sphorylates PtdIns3P, and when hypoosmotic stress is induced inCOS7 cells (a condition that increases PtdIns(3,5)P2 levels), MTMR2relocalizes to the membranes of intracellular vacuoles formedunder this condition (Berger et al., 2003; Franklin et al., 2011).

MTMR13 is a catalytically inactive phosphatase of 1849 aminoacids with a PH-GRAM domain, a PTP domain with substitutions inthe Cys and Arg residues of the Cys-X5-Arg site for catalyticactivity, and a coiled-coil domain and PDZ-BD as in MTMR2.




G Model


MTMR13 also possesses a DENN (differentially expressed inneoplastic versus normal cells) domain at the N-terminus and acanonical PH domain at the C-terminus (Azzedine et al., 2003).Recent studies have revealed that DENN domains interact directlywith Rab proteins and that they are Rab-specific GEFs, thusregulating Rab function (Allaire et al., 2010; Marat et al., 2011;Marat and McPherson, 2010; Niwa et al., 2008; Yoshimura et al.,2010). MTMR13 has GEF activity towards Rab28 (Yoshimura et al.,2010). Rab28 is a poorly characterized small GTPase that co-localizes with endosomal sorting complex required for transport I(ESCRT-I) in the unicellular organism Trypanosoma brucei, where itmay play a role in the turnover of ubiquitinated endocytosedproteins and in the lysosomal delivery of cargo, suggesting thatMTMR13 could also be involved in endocytic traffic (Lumb andField, 2010). Interestingly, MTMR2 and MTMR13 interact and formheterotetramers by the association of homodimers, consisting oftwo MTMR2 and two MTMR13 molecules (Berger et al., 2006a;Bolis et al., 2007; Robinson and Dixon, 2005). MTMR13 is thoughtto regulate both MTMR2 subcellular localization and phosphataseactivity, increasing the enzymatic activity of MTMR2 towardsPtdIns3P and PtdIns(3,5)P2 (Berger et al., 2006a).

Although ubiquitously expressed, mutations in either MTMR2

or MTMR13 cause CMT type 4B1 and 4B2 neuropathy, respectively(Azzedine et al., 2003; Bolino et al., 2000; Senderek et al., 2003b).CMT4B1-associated mutations are MTMR2 loss-of-function muta-tions: base-pair insertions or deletions that cause frameshifts,missense mutations that create stop codons or amino acid changes(Bolino et al., 2000; Previtali et al., 2007). Most of the identifiedMTMR2 mutations affect the PTP domain, resulting in loss ofenzymatic activity (Berger et al., 2002; Parman et al., 2004;Previtali et al., 2007). Despite the ubiquitous expression of MTMR2,Schwann-cell-specific depletion of MTMR2 is sufficient for thedevelopment of myelin outfolding in transgenic mice (Bolino et al.,2004; Bolis et al., 2005; Bonneick et al., 2005). Since dysmyelina-tion and axonopathy are not observed in the motor-neuron-nullmouse but loss of MTMR2 phosphatase activity in Schwann cells issufficient and necessary to cause myelin outfolding as in CMT4B1,MTMR2 has a Schwann-cell-autonomous role (Bolis et al., 2005).However, because MTMR2 is expressed at high levels by peripheralneurons and axonopathies are not easily reproduced in mice, apotential cell-autonomous role of MTMR2 in neurons too cannot beexcluded (Berger et al., 2002; Suter and Scherer, 2003). CMT4B2results instead from the loss of the DENN domain of MTMR13(Senderek et al., 2003b). The precise mechanisms by which MTMRmutations lead to CMT neuropathy are not known; however, it isworth noting that the DENN domain of MTMR13 interacts with Rabproteins, implying a link between CMT disease mutations andalterations in endosomal trafficking.

Although the role of MTMR2 and MTMR13 in intracellulartrafficking and the exact nature of the intracellular compartmentsto which they are associated remain to be assessed, several of theirinteracting partners have been identified. MTMR2 associates withMTMR13 (Robinson and Dixon, 2005), and with the neurofilamentlight chain (NEFL) in neurons and Schwann cells (Previtali et al.,2003). Interestingly, mutations in the gene encoding the NEFLprotein also cause CMT disease (Abe et al., 2009; Jordanova et al.,2003; Shin et al., 2008a; Yum et al., 2009). MTMR2 is ubiquitouslyexpressed, whereas NEFL is specifically expressed in the nervoussystem. Thus, the role of the MTMR2/NEFL interaction in neuronsand/or Schwann cells may explain why mutations in theubiquitously expressed MTMR2 specifically affect the nerves(Previtali et al., 2003). Interactions between MTMR2 and Dlg1(discs large 1, also known as SAP97, synapse-associated protein 97)or PSD-95, two members of the membrane-associated guanylatekinase (MAGUK) family, have also been reported (Bolino et al.,2004; Lee et al., 2010). Dlg1 is a scaffolding protein which links


transmembrane proteins with the intracellular cytoskeleton. It islocated at adherens junctions of epithelial cells and at pre- andpostsynaptic sites in neurons (Fujita and Kurachi, 2000). Dlg1interacts with kinesin 13B (kif13B) and the Sec8 exocyst complexcomponent in Schwann cells (Bolis et al., 2009). Kif13B is a plus-end motor protein that transports PtdIns3P-containing vesiclesalong microtubules in neurons, whereas the exocyst is anoctameric protein complex that tethers secretory vesicles at theplasma membrane for exocytosis (He and Guo, 2009; Horiguchiet al., 2006). A model has been proposed whereby kif13B transportsDlg1 to sites of membrane remodeling to control and balancemyelination: interaction of Dlg1 with Sec8 would promotemembrane addition, whilst interaction of Dlg1 with the phospha-tase MTMR2 would negatively regulate membrane formation(Bolino et al., 2004; Bolis et al., 2009). Therefore, loss of theMTMR2/Dlg1 interaction in Schwann cells may impair membranehomeostasis, leading to myelin defects (Bolino et al., 2004).

4.2.2. FIG4

FIG4 is a PtdIns(3,5)P2 5-phosphatase that dephosphorylatesPtdIns(3,5)P2 at the 5th position of the inositol ring converting it toPtdIns3P (Fig. 2) (Gary et al., 2002; Marks, 2008; Rudge et al., 2004).

It contains a polyphosphoinositide phosphatase domain calledthe Sac1 domain (Gary et al., 2002). Fig4p (Fig4 in yeast) is requiredto activate Fab1p (the PtdIns3P 5-kinase that generatesPtdIns(3,5)P2) and it physically associates with Fab1p and Vac14pin a protein complex that regulates the overall concentration ofPtdIns(3,5)P2. This complex, that also includes Vac7p and Atg18p,works at the vacuole membrane (the yeast vacuole corresponds tolate endosomes/lysosomes in mammalian cells) to sustain bothbasal and hyperosmotic shock-induced PtdIns(3,5)P2 synthesis(Botelho et al., 2008; Jin et al., 2008b; Michell and Dove, 2009;Sbrissa et al., 2007). Vac14p (also known as ArPIKfyve in mammals)and Vac7p are Fab1p activators which regulate PtdIns(3,5)P2

synthesis and turnover (Bonangelino et al., 2002; Duex et al., 2006;Efe et al., 2007). Interestingly, mutation in the VAC14 mouse geneinduces neurodegeneration and neurological defects similar tothose produced by the lack of FIG4 (Chow et al., 2007; Fergusonet al., 2009). In addition, deletion of FAB1, VAC14 or VAC7, as well asyeast cells lacking Atg18p, show enlarged vacuoles and acidifica-tion defects similar to FIG4 deletion (Bonangelino et al., 2002; Doveet al., 2002; Efe et al., 2007; Gary et al., 2002; Rudge et al., 2004). Inyeast, the transport of membrane proteins from the vacuole isdependent on PtdIns(3,5)P2. Therefore, the enlarged vacuole couldoriginate from a failure in membrane recycling from the vacuole tothe pre-vacuolar endosomes (Dove et al., 2004). Concordantly,PIKfyve (the equivalent of Fab1p in mammals) regulates endo-some-to-TGN retrograde transport in mammalian cells (Ikonomovet al., 2003; Rutherford et al., 2006).

Chow et al. found a spontaneous mutation of the FIG4 gene inthe mouse that is responsible for the ‘pale tremor’ phenotype, sonamed because of the light pigmentation and the severe tremorand abnormal gait (Chow et al., 2007). As in the yeast studies, FIG4-deficient mice show reduced levels of PtdIns(3,5)P2 and enlargedlate endosomes–lysosomes. The observation of the ‘pale tremormouse’ phenotype allowed the identification of FIG4 mutations inpatients with CMT neuropathy. Indeed, many symptoms in themutant mice, such as neuronal degeneration in the central andperipheral nervous systems, large myelinated axons in the sciaticnerve and large vacuole accumulation within neurons thatprecedes neuronal loss, are similar to those of humans withCMT4J disease (Chow et al., 2007; de Leeuw, 2008). But how domutations in FIG4 cause neurodegeneration? The endosome-lysosome system performs a key role in membrane and proteinhomeostasis and controls their degradation. A correct trafficking isessential for cell survival. Alterations in this process particularly




G Model


affect neurons with long axons (Baloh, 2008). Abnormal transportof intracellular organelles has been observed by time-lapseimaging in fibroblasts from CMT4J patients, suggesting that adefective trafficking of intracellular organelles due to obstructionby endosomes could be a potential mechanism causing thisdisorder (Zhang et al., 2008a). FIG4 has a role in the regulation ofPtdIns(3,5)P2 and proper PtdIns(3,5)P2 levels are essential forretrograde membrane trafficking from lysosomes and late endo-somes (Michell and Dove, 2009; Rutherford et al., 2006). Alterationin PtdIns(3,5)P2 levels due to FIG4 mutations could thereforeinhibit this recycling, leading to the accumulation of largeendosomes (Zhang et al., 2008a). In addition, it has been observedthat FIG4 exists in complex with ArPIKfyve in mammalian cells andthat ArPIKfyve knockdown significantly reduces FIG4 proteinlevels, suggesting a role for ArPIKfyve in the attenuation of FIG4proteasome-dependent degradation (Ikonomov et al., 2009, 2010;Sbrissa et al., 2007). It has been hypothesized that, when associatedwith ArPIKfyve, FIG4 is protected from degradation, whereas whenit is in isolation, FIG4 is unfolded and therefore easily degraded(Ikonomov et al., 2010). A mutation at position 41 in FIG4 presentin CMT4J patients appears to be responsible for the loss ofArPIKfyve protective activity against degradation. The resultingrapid degradation of FIG4 in these patients might alterPtdIns(3,5)P2 homeostasis, thus causing defects in membranetrafficking (Chow et al., 2007; Ikonomov et al., 2010).

Importantly, alterations in PI signaling and vesicle traffickinghave been implicated in other forms of CMT disease. Altered levelsof PtdIns(3,5)P2 and PtdIns3P, due to mutations in MTMR2 andMTMR13 which dephosphorylate PtdIns3P and PtdIns(3,5)P2 at the3rd position of inositol, cause CMT4B1 and CMT4B2, respectively,characterized by excessive myelin outfolding probably due to adefective transport towards myelin sheaths (Nicot and Laporte,2008). It has recently been demonstrated that loss of FIG4 rescuesmyelin outfolding caused by MTMR2 deficiency in Schwann cellsas well as neurons, probably balancing the increase ofPtdIns(3,5)P2 in Mtmr2-null cells and thus reducing myelinoutfolding (Vaccari et al., 2011). The presence of cytoplasmicinclusions in Schwann cells and the typical demyelinating featuresof CMT4J patients support a Schwann-cell-autonomous role forFIG4 (Scherer and Wrabetz, 2008; Vaccari et al., 2011; Zhang et al.,2008a).

Neurodegeneration may be related not only to alterations in thedelivery of membrane components from endosomes but also toabnormal accumulation of proteins due to impaired degradation.Indeed, neurons are long-lived, terminally differentiated cells, andaccumulation of components that should be degraded easilycauses damage in these cells that cannot renew themselves. It isknown that alterations in the endosomal/degradative pathwaylead to neurodegeneration in other disorders such as Niemann–Pick type C disorder (Karten et al., 2009). In addition, the lateendosomal–lysosomal system has a role in autophagy, the processby which cells degrade their own components. Autophagy isaltered in many human diseases, including several neurodegener-ative disorders where the accumulation of misfolded proteins is aresult from defects in autophagy (Huang and Klionsky, 2007;Martinez-Vicente and Cuervo, 2007). Vps34 and its productPtdIns3P are involved in the control of autophagic vesicles, andPtdIns(3,5)P2 has an essential role in autophagy in the mammaliannervous system (Ferguson et al., 2009; Petiot et al., 2000; Simonsenand Tooze, 2009). Interestingly, in mice with mutations in FIG4 andVAC14 that cause severe neurodegeneration, a reduced number ofmyelinated axons in the sciatic nerve and loss of neurons areobserved, and autophagy intermediates accumulate in the brainand spinal cord. Enlarged late endosomes/lysosomes are present inthe cytoplasm of cultured fibroblasts and neurons from these miceand autophagy appears to be blocked. Concordantly, Ferguson et al.


have recently proposed that CMT4J represents a type ofautophagy-related disease caused by mutations in the autophagymachinery itself (Ferguson et al., 2009, 2010).

4.3. Defects in cytoskeletal transport: KIF1B, NEFL and FGD4/Frabin

4.3.1. KIF1B

KIF1Bb is a plus-end-directed motor that transports synapticvesicle precursors in the axon from the cell body to the synapse. Itis generated by a splicing variation in the cargo-binding domain ofthe KIF1B gene. KIF1Bb contains a C-terminal PH domain with apreference for binding to PtdIns(4,5)P2, a phospholipid widelydistributed throughout the plasma membrane, Golgi, endosomesand ER, as well as within the nucleus (Hirokawa et al., 2010; Wattet al., 2002). KIF1Bb is expressed in both neurons and glia and it isessential for proper localization of myelin protein mRNA inzebrafish oligodendrocytes in order to elaborate the correctamount of myelin around axons (Lyons et al., 2009). It also actsas a tumor suppressor and induces apoptosis in neurons(Munirajan et al., 2008; Schlisio et al., 2008). KIF1Bb is essentialfor the transport of DENN/MADD and Rab3 vesicles (Niwa et al.,2008). Rab3 is a small GTPase located to synaptic vesicles that isimplicated in synaptic vesicle dynamics and exocytosis (Geppertet al., 1997; Takai et al., 1996). DENN/MADD is a Rab3 GEF,designated as GEP, consisting of an N-terminal MADD domain anda conserved C-terminal domain (Niwa et al., 2008; Sakisaka andTakai, 2005). DENN/MADD binds to the stalk domain of KIF1Bb andinteracts with Rab3 on cargo membranes, therefore acting as alinker between KIF1Bb and Rab3-carrying vesicles (Niwa et al.,2008).

Like Kif1b knockout mice, DENN/MADD knockout mice die afterbirth because of a respiratory problem and exhibit a reducednumber and size of synaptic vesicles (Tanaka et al., 2001; Zhaoet al., 2001). In kif1b heterozygous mice, both the number ofsynapses and the density of synaptic vesicles are reduced,consistent with a defect of synaptic vesicle precursor axonaltransport (Zhao et al., 2001). A low survival rate of kif1b�/� neuronsfrom mice co-cultured with wild type glia has been reported,suggesting that KIF1Bb acts cell-autonomously in neurons (Zhaoet al., 2001). A mutation of KIF1Bb has been shown to cause type2A of CMT disease in a Japanese family. CMT2A patients have aloss-of-function point mutation in the ATP-binding site of themotor region of KIF1Bb that causes significant reduction in ATPaseand in vitro motor activities (Zhao et al., 2001). However, the factthat KIF1Bb mutation causing CMT2A has been identified in only asingle family questions whether this gene should be considered asa significant candidate for the etiology of CMT2 (Zuchner andVance, 2006).

4.3.2. NEFL

Mutations in the neurofilament light polypeptide gene (NEFL)cause autosomal dominant axonal CMT2 (CMT2E) or demyelinat-ing CMT1 (CMT1F) (De Jonghe et al., 2001; Jordanova et al., 2003;Mersiyanova et al., 2000; Shin et al., 2008a). Recent reports showthat NEFL mutations can also cause an autosomal recessive form ofCMT neuropathy (Abe et al., 2009; Yum et al., 2009). In thedemyelinating forms of CMT disease due to NEFL mutations, thedemyelination may only be a consequence of a primary axono-pathy (Fabrizi et al., 2004, 2007a). Neurofilaments play importantroles in the maintenance of the cytoskeleton and axonal structure.Therefore, it is not surprising that NEFL mutations can cause anaxonal neuropathy. Indeed, CMT disease-associated NEFL muta-tions affect the formation of neurofilament networks, the assemblyof neurofilaments and both anterograde and retrograde transport(Brownlees et al., 2002; Perez-Olle et al., 2002, 2005). Somemutations can also cause fragmentation of the Golgi apparatus,




G Model


altered mitochondrial distribution and degeneration of neuriticprocesses in cultured neuronal cells (Brownlees et al., 2002; Perez-Olle et al., 2005). Furthermore, mutations result in the formation ofneurofilament aggregates (Fabrizi et al., 2004; Perez-Olle et al.,2002; Sasaki et al., 2006). Accumulation of neurofilaments mayprevent the transport of proteins and cellular components eitherby creating a barrier or by trapping them within the inclusions.Also, it has been suggested that NEFL mutants may disrupt theinteractions with mitochondria and the formation of neurofila-ment aggregates traps mitochondria within these inclusions(Perez-Olle et al., 2005). Mitochondria accumulation couldtherefore interfere with the correct supply of energy to the restof the cell.

Neurofilament transport is dependent on the motor proteinsKIF5A and dynein, and both the kinesin and dynein families ofmotors require ATP (Uchida et al., 2009; Wagner et al., 2004). NEFL

mutations could perturb the correct functioning of the motors orthe interaction with molecular motors. It is interesting to note thatmutations in KIF5A disrupt neurofilament transport and causehereditary spastic paraplegia (Musumeci et al., 2011; Wang andBrown, 2010). In addition, mice null for KIF5A display abnormalaccumulations of neurofilaments (Xia et al., 2003). As mentioned inthe previous section, mutation of the molecular motor KIF1Bbcauses another form of type 2 CMT disease, providing furtherevidence that alterations of molecular motors, and in general ofaxonal transport, result in neurodegeneration (Xia et al., 2003;Zhao et al., 2001). Axonal transport is essential for the survival ofneurons and it is responsible for the transport of organelles andligands, such as neurotrophins and other growth factors, andtransport defects appear to be a cause for the development ofneuropathies (De Vos et al., 2008; Goldstein and Yang, 2000).

Disruption of the assembly and aggregation of neurofilamentsthat interferes with axonal transport is also induced by expressionof mutant HSP27 (or HSPB1), a chaperone protein that causes anautosomal recessive form of distal motor neuropathy in CMT2F(Ackerley et al., 2006; Lin and Schlaepfer, 2006; Zhai et al., 2007). Itis not surprising that mutant HSP27 causes protein aggregationand loss of viability of transfected neuronal cells, since its normalfunction is to bind and prevent misfolding and aggregation ofnascent proteins and it is known to interact with intermediatefilaments (Perng et al., 1999; Vos et al., 2008).

NEFL interacts with MTMR2 in Schwann cells as well as inneurons (Previtali et al., 2003). Interestingly, mutations in MTMR2

cause an autosomal recessive demyelinating form of CMTneuropathy referred to as CMT4B (Bolino et al., 2000). As aconsequence of the interaction with NEFL, MTMR2 mutants canlead to neurofilament aggregation (Goryunov et al., 2008). Theexact relationship between MTMR2 catalytic activity and NEFLaggregation is not known. However, catalytically inactive CMTdisease-related MTMR2 mutants lead to NEFL assembly defectsand to pathologies similar to the one caused by NEFL mutations,suggesting that MTMR2 and NEFL may function in a commonpathway in the development and maintenance of peripheral axons.

4.3.3. FGD4/Frabin

FGD4/Frabin (FYVE, RhoGEF and PH domain-containing protein4) is a member of the Cdc42 GEF family (Obaishi et al., 1998).Cdc42, together with the Rac and Rho subfamilies, belongs to theRho family of small G-proteins, important regulators of actincytoskeleton organization. Cdc42 regulates actin cytoskeletondynamics influencing cell migration, adhesion and cytokinesis. Itsactivity is tightly regulated by the interconversion between a GDP-bound inactive and a GTP-bound active form (Heasman and Ridley,2008; Jaffe and Hall, 2005). GEFs, like Frabin, activate Cdc42through the binding of GTP (Umikawa et al., 1999). Frabin caneither activate Cdc42 directly, Rac indirectly, or its activity can be


Cdc42/Rac independent (Ikeda et al., 2001; Nakanishi and Takai,2008; Ono et al., 2000; Umikawa et al., 1999).

In fibroblasts, Cdc42 activation by Frabin causes filopodiaformation, while Rac activation induces the formation of lamelli-podia (Ono et al., 2000). In addition, Frabin can activate both Cdc42and Rac, inducing microspike formation (Umikawa et al., 1999;Yasuda et al., 2000). Mutations in FGD4 are associated with CMT4H,an autosomal recessive demyelinating form of CMT disease,suggesting that Frabin is involved in the myelination process.Although the molecular mechanisms by which FGD4 mutationscause CMT4H are completely unknown (Delague et al., 2007;Stendel et al., 2007), the molecular structure of Frabin allows forspeculation. FGD4 consists of an F-actin-binding (FAB) domain atthe N-terminal region, important for the association with F-actin,followed by a Dbl homology (DH) domain, and two PH domainsseparated by a FYVE domain (Nakanishi and Takai, 2008; Obaishiet al., 1998). DH domains are conserved in the GEFs for Rhoproteins, and when in proximity to a PH domain, they areimportant for the GEF nucleotide-exchange activity (Rossmanet al., 2005). Interestingly, PH domains bind PIs on membranes andFYVE domains associate with PtdIns3P, a phosphatidylinositolmainly localized on early endosomes and MVBs (Kutateladze,2006; Lemmon, 2008). Therefore, the presence of both PH andFYVE domains in Frabin suggests that it may act as a bridgebetween membranes containing PtdIns3P and actin. The fact thatCdc42 functions in vesicle transport by regulating actin supportsthis hypothesis (Harris and Tepass, 2010; Luna et al., 2002; Muschet al., 2001). Actin is known to be important for vesicle traffickingin several ways, and it provides tracks for motor protein-basedvesicle transport. In mammalian cells, a significant fraction ofCdc42 localizes to the Golgi apparatus where it binds to the coatprotein I (COPI) vesicle coat protein, thus promoting vesicleformation and regulating actin dynamics (Chen et al., 2005, 2004a;Luna et al., 2002; Matas et al., 2004). In addition, at the cell cortex,Cdc42 promotes actin assembly, thereby regulating exocytosis(Momboisse et al., 2009; Zhang et al., 2008b). Finally, the PH andFYVE domains may also connect Frabin to MTMRs by mediating thebinding to myotubularin substrates and products. The finding thatnerve biopsy samples from patients with MTMR-associated CMTneuropathy show abnormalities in myelin folding similar to thoseobserved in CMT4H patients is in line with this hypothesis (Stendelet al., 2007). In conclusion, mutations of Frabin could affect PImetabolism or cytoskeleton dynamics, thereby interfering withmembrane traffic and/or myelin deposition.

4.4. Defects in the regulation of membrane traffic events: Rab7,

NDRG1 and SH3TC2

4.4.1. Rab7

Rab7 is a small GTPase of the Rab family, first identified in a ratliver cell line (Bucci et al., 1988). Rab7 is localized to lateendosomes and lysosomes and regulates late endocytic traffic. It isthus a key protein for the biogenesis of lysosomes andphagolysosomes, and for the maturation of late autophagicvacuoles (Bucci et al., 2000; Harrison et al., 2003; Jager et al.,2004) (Figs. 3 and 4). Rab7 is also important for cell nutrition andapoptosis (Edinger et al., 2003; Snider, 2003) (Fig. 4).

A number of Rab7 effector proteins have been identified. Forinstance, Rab7 recruits RILP (Rab-interacting lysosomal protein) onendosomal membranes, which in turn recruits the dynein/dynactin complex, thereby allowing microtubule minus-end-mediated transport of endosomes and lysosomes (Cantalupoet al., 2001; Harrison et al., 2003; Johansson et al., 2007). Also,FYCO1 (FYVE and coiled-coil domain containing 1) forms acomplex with Rab7 and directs plus-end transport of autophago-somes along microtubules (Pankiv et al., 2010). Rab7 also recruits



Fig. 3. Role of endocytic membrane traffic proteins involved in CMT disease. DNM2 is important for budding of vesicles from the plasma membrane. Rab7 controls transport

from late endosomes (LE) to lysosomes (Lys). LRSAM1 binds and ubiquitinates Tsg101, a protein involved in formation of MVBs and in the sorting of signaling receptors in

intraluminal vesicles in order to be degraded; ubiquitination of Tsg101 inactivates its sorting function and thus inhibits signaling receptor degradation. A role for LITAF/

SIMPLE in the sorting and degradation of signaling receptors is strongly suggested by the finding that this protein is ubiquitinated by Nedd4 and then interacts with Tsg101.


G Model


the retromer complex to endosomes, and interacts with hVps34/p150 regulating PI 3-kinase activity in the endo-lysosomalpathway (Rojas et al., 2008; Stein et al., 2003).

Given the importance of this small GTPase in many cellularfunctions (Fig. 4) and its multiple interactions, it is not surprisingthat Rab7 mutations underlie neuronal diseases. Indeed, fourmissense mutations in the rab7 gene on chromosome 3q21 areassociated with CMT2B (Chiariello et al., 1998; Houlden et al.,2004; Meggouh et al., 2006; Verhoeven et al., 2003a). The fourCMT2B-causing Rab7 mutant proteins have been characterizedbiochemically and show very similar biochemical properties (DeLuca et al., 2008; Spinosa et al., 2008). Indeed, they have increasedKoff for nucleotides, and these altered nucleotide dissociation ratesin turn negatively affect GTPase activity per binding event (De Lucaet al., 2008; Spinosa et al., 2008). In particular, the GDP dissociationrate is strongly increased and, accordingly, the mutant proteins arepredominantly in the GTP-bound form (De Luca et al., 2008;Spinosa et al., 2008). In addition, their activation is not dependenton GEFs, and they show enhanced interaction with a number ofeffector proteins (McCray et al., 2010; Spinosa et al., 2008).Furthermore, they are able to rescue Rab7 function following Rab7


silencing, suggesting that they behave as active mutant proteins(De Luca et al., 2008; Spinosa et al., 2008).

In neurons, Rab7 regulates long-range retrograde axonaltransport of neurotrophins and neurotrophin receptors (Deinhardtet al., 2006). It also controls endocytic traffic and neuritogenicsignaling of the nerve growth factor receptor TrkA. Indeed, afterneuronal stimulation by nerve growth factor (NGF), Rab7 interactswith TrkA with effects on receptor signaling and neurite outgrowth(Saxena et al., 2005a). NGF promotes neuronal survival and neuriteoutgrowth by binding and activating its receptor TrkA on axon tips(Kaplan et al., 1991; Klein et al., 1991). Upon NGF binding, TrkA isinternalized into endosomes and retrogradely transported, con-tinuing to signal (Ehlers et al., 1995; Grimes et al., 1997, 1996).Signaling endosomes containing activated TrkA are then trans-ported retrogradely over long distances from the axonal synapse tothe cell body (Delcroix et al., 2003; Ehlers et al., 1995; Grimes et al.,1997; Howe and Mobley, 2005; Saxena et al., 2005b). Interestingly,inhibition of Rab7 activity causes the accumulation of TrkA withinendosomes and enhanced TrkA signaling in NGF-stimulated PC12cells, leading to an increase in neurite outgrowth (Saxena et al.,2005a). CMT2B-associated Rab7 mutants are still able to interact



Fig. 4. Intracellular trafficking proteins involved in CMT neuropathy. DNM2 regulates vesicle budding. KIF1B controls vesicle motility on microtubules. LITAF/SIMPLE and

LRSAM are present in the endocytic pathway and probably regulate protein degradation. Myotubularin-related proteins (MTMR2 and MTMR13) and FIG4 regulate PI

metabolism at the level of early endosomes and late endosomes, respectively. Rab7 is present on late endosomes and regulates transport to lysosomes. SH3TC2 regulates

endosomal recycling together with Rab11, while NDRG1 regulates membrane traffic at the level of early endosomes together with Rab4 and PRA1. HSPs regulate proteasomal

degradation and associate with neurofilaments and actin filaments. FGD4 associates with and regulates actin filaments. MFN2 and GDAP regulate mitochondrial dynamics

and mitochondrial axonal transport.


G Model


with TrkA after NGF stimulation, but TrkA phosphorylation isstrongly enhanced and the downstream signaling pathways arealtered, leading to the inhibition of neurite outgrowth in PC12 cells(BasuRay et al., 2010; Cogli et al., 2010). Therefore, Rab7 plays animportant role in controlling TrkA signaling by regulating itsendosomal traffic, possibly through control of the endosomalsignaling time, and subsequently promoting neurite outgrowth.Defects in Rab7 activity may interfere with the endosomalresidence time of TrkA and thereby with the signal duration.However, this may not be the only pathogenic effect of Rab7mutations, since defective neurite outgrowth has also beenobserved in Neuro2A cells where TrkA signaling is not involved(Cogli et al., 2010). This suggests that another alternative pathwaymay contribute to CMT2B. For instance, Rab7 could interact with


an effector selectively expressed in peripheral neurons only, thusregulating a cell-type-specific pathway (Cogli et al., 2009). Notably,impaired neurite outgrowth has also been observed in other celllines where the effect was reversed by valproic acid, indicating away to overcome the inhibition of neurite outgrowth (Yamauchiet al., 2010).

Rab7 is a ubiquitously expressed protein (Bucci et al., 1988;Verhoeven et al., 2003a). Why should mutations in a ubiquitousprotein selectively affect a specific cell type? It is important to notethat axonal transport is very important for neuronal functions, andaxons, especially in peripheral neurons, can be particularly long,more than one meter. Therefore, mutations in membranetrafficking may have stronger effects on such cells where thetransport of cellular components needs to cover large distances




G Model


compared to other cell types. Also, CMT2B patients do not showany developmental defects, indicating that the inhibition of neuriteoutgrowth in this case might affect neuroregeneration, whichbecomes less successful with age, explaining the late onset ofCMT2B (Perlson et al., 2004; Wu et al., 2007). Neuroregeneration ofaxons consists of the formation of a new growth cone at the cut tipof the axon after damage. An increase of intracellular calciumlevels, intracellular signaling pathways, and local protein synthesisand degradation are involved in the formation of the new growthcone (Chierzi et al., 2005; Gitler and Spira, 1998; Liu and Snider,2001; Verma et al., 2005; Wu et al., 2007). If Rab7 mutant proteinsaffect axonal regeneration, the specific effect on peripheralneurons could be due to the fact that axonal regeneration inmammals occurs mainly in the peripheral nervous system(Hilliard, 2009; Shim and Ming, 2010). It is worth noting thataberrations of macroautophagy have been observed in severalneurodegenerative disorders. Thus, as Rab7 regulates the matura-tion of autophagic vacuoles, CMT disease-causing mutations in theRab7 protein could also affect this pathway (Garcıa-Arencibia et al.,2010; Jager et al., 2004; Martinez-Vicente et al., 2010; Vogiatziet al., 2008; Yu et al., 2005).

4.4.2. NDRG1

Mutations in N-myc downstream regulated gene 1 (NDRG1) areresponsible for CMT4D, an autosomal recessive demyelinatingneuropathy (Hunter et al., 2003; Kalaydjieva et al., 2000, 1996,1998). The 43 kDa NDRG1 protein is a member of the NDRG familycharacterized by an a/b hydrolase region without presenting ahydrolytic catalytic site (Melotte et al., 2010; Shaw et al., 2002).NDRG1 is ubiquitously expressed, with high levels in theperipheral nervous system where it is confined to Schwann cells(Berger et al., 2004; King et al., 2011). NDRG1 is repressed by N-myc during mouse development (Shimono et al., 1999), upregu-lated during cellular differentiation (van Belzen et al., 1997) andpositively regulated by p53 which leads to reduced expression inp53-dependent tumors (Kurdistani et al., 1998). It has beenproposed as a metastasis suppressor gene (Bandyopadhyay et al.,2006; Guan et al., 2000), and to function in the ER stress response(Segawa et al., 2002). However, how NDRG1 mediates its multiplefunctions remains largely unknown.

Myelinating Schwann cells and oligodendrocytes expressNDRG1; however, sensory and motor neurons as well as theiraxons lack NDRG1 (Berger et al., 2004). NDRG1 mutations inCMT4D patients lead to a Schwann-cell-autonomous phenotyperesulting in defective myelination with secondary axonal degen-eration, indicating a role for the wild type protein in thedevelopment and/or maintenance of the myelin sheaths inperipheral nerves (Berger et al., 2004; Okuda et al., 2004). Sincemyelin biogenesis involves coordinated activities of both theendocytic and the exocytic pathways (Anitei and Pfeiffer, 2006;Trajkovic et al., 2006; Winterstein et al., 2008), it is not surprisingthat several NDRG1 interaction partners with various roles inintracellular trafficking have been described, highlighting that themechanism of CMT4D pathogenesis is connected to the alterationsin the trafficking inside Schwann cells (Hunter et al., 2005;Kachhap et al., 2007).

NDRG1 localizes to the nucleus and the cytoplasm. Itsassociation with adherens junctions suggests a functional involve-ment in the E-cadherin/catenin complex (Berger et al., 2004;Lachat et al., 2002; Tu et al., 2007). E-cadherin is a 120 kDatransmembrane glycoprotein present in adherens junctions on thesurface of epithelial cells (Whittard et al., 2002). Its extracellulardomain forms a homodimer with E-cadherin of neighboring cells inthe presence of extracellular calcium (Koch et al., 1997; Nagaret al., 1996). The cytoplasmic domain of E-cadherin interacts witha-, b- and g-catenins (Kobielak and Fuchs, 2004; Piepenhagen and


Nelson, 1993). The assembly and turnover of the E-cadherinmolecule involve its phosphorylation, ubiquitination, internaliza-tion by endosomes, and subsequent lysosomal or proteasomaldegradation or recycle back to the cell surface (Fujita et al., 2002).E-cadherin trafficking from the cell surface to the endosomes andback is central to the dynamics and stability of the adhesioncomplex (Le et al., 1999). It has been demonstrated that NDRG1 is aRab4a effector involved in the recycling of E-cadherin. NDRG1 isrecruited from the cytosol to perinuclear recycling/sortingendosomes by binding to PtdIns4P (Kachhap et al., 2007). Rab4,together with Rab11, is involved in the regulation of endosomalrecycling back to the plasma membrane. They also participate inadherens junction dynamics by interacting with a- and b-catenin(Mruk et al., 2007; Sonnichsen et al., 2000). Interestingly, aninvolvement of the cadherin/catenin complex in the initiation ofmyelination at the Schwann cell-axon interface has recently beendemonstrated (Lewallen et al., 2011). NDRG1s role in CMT4Dpathogenesis therefore appears to be connected to its function incellular trafficking. Additional evidence is provided by theidentification of the trafficking protein prenylated Rab acceptor1 (PRA1) as an interacting partner of NDRG1 (Hunter et al., 2005).PRA1 is required for vesicle formation from the Golgi apparatus,and interacts with members of the Rab family which regulatetransport between organelles, including Rab7 and Rab4 (Bucciet al., 1999; Gougeon et al., 2002). Interestingly, as mentionedearlier, Rab7 plays a crucial role in late endosomal traffic and ismutated in another form of CMT neuropathy, CMT2B, and Rab4interacts with NDRG1 (Hunter et al., 2005; Kachhap et al., 2007;Verhoeven et al., 2003a; Vitelli et al., 1997). NDRG1 may thus beanother member of the group of CMT disease-associated proteinswith a role in endosomal transport.

Other NDRG1-interacting proteins are the apolipoproteins A-I(APOA1) and A-II (APOA2), suggesting a role for NDRG1 in lipidtransport (Hunter et al., 2005). These proteins are components ofhigh-density lipoproteins that regulate lipid distribution withinthe body (Schmitz and Grandl, 2009). The integrity of this processis very important. Indeed, genetic disorders of cholesteroltransport, such as APOA1 deficiency, cause peripheral neuropathy(Ng et al., 1996). Because myelinating Schwann cells have a highdemand for lipids, CMT4D may be a trafficking disorder in thesecells, resulting in abnormal targeting of lipids/proteins to themyelin membrane (Hunter et al., 2005).

4.4.3. SH3TC2

CMT disease type 4C (CMT4C) is an autosomal recessive form ofdemyelinating neuropathy characterized by mutations in SH3TC2

(Azzedine et al., 2006; Senderek et al., 2003a). CMT4C mutationslead to truncations at the N- and C-termini and also to amino acidsubstitutions throughout the SH3TC2 protein. The 1288 amino acidSH3TC2 protein is strongly expressed in neural tissues, includingperipheral nerve tissue. It contains two N-terminal SH3 domainsand 10 C-terminal tetratricopeptide repeat (TPR) domains(Senderek et al., 2003a). SH3 domains bind to proline-rich regionsof other proteins and are involved in clathrin-mediated vesicleendocytosis and synaptic vesicle recycling (Kim and Chang, 2006;McPherson, 1999). TPR domains, usually present in tandemrepeats, mediate protein-protein binding and multiprotein com-plex formation (Blatch and Lassle, 1999). SH3TC2 localizes torecycling endosomes and interacts with the small GTPase Rab11(Arnaud et al., 2009; Roberts et al., 2010; Stendel et al., 2010).Rab11 regulates the recycling of internalized receptors andmembrane back to the cell surface (Ullrich et al., 1996).Interestingly, SH3TC2 mutants causing CMT4C are unable toassociate with Rab11, with consequent mistargeting from recy-cling endosomes towards the cytosol (Roberts et al., 2010; Stendelet al., 2010).




G Model


Schwann cell dysfunction and defects in myelination have beenobserved in SH3TC2 knockout mice. Furthermore, impairedmyelination in primary rat Schwann cells expressing the dominantnegative Rab11 has been reported. These findings suggest thatSH3TC2, together with Rab11, regulates Schwann cell myelination(Arnaud et al., 2009; Stendel et al., 2010).

Recycling endosomes have been shown to sort and redirectsome myelin components to the plasma membrane duringmorphogenesis of the myelin sheath in oligodendrocytes. Howev-er, the molecular pathways regulating vesicular transport duringmyelination are largely unknown (Winterstein et al., 2008). TheSH3TC2/Rab11 interaction is therefore relevant for peripheralnerve pathophysiology, highlighting the important role of theendosomal recycling pathway in Schwann cell myelination(Stendel et al., 2010).

4.5. Defects in the regulation of protein degradation: HSPs, LRSAM1

and LITAF/SIMPLE

4.5.1. HSPs

Mutations in the genes HSPB1 (HSP27) and HSPB8 (HSP22), twomembers of the small HSP superfamily, have been associated withCMT2F and CMT2L, respectively (Evgrafov et al., 2004; Irobi et al.,2004; Tang et al., 2005). HSP22/HSPB8 is ubiquitously expressed,with high expression detected in the spinal cord and in motor andsensory neurons (Irobi et al., 2004). Immunolocalization studies inneuroblastoma cell lines have shown that HSP22 is predominantlylocalized to the plasma membrane. Furthermore, it possesseschaperone-like activity and prevents protein aggregation (Carraet al., 2005; Chowdary et al., 2004, 2007; Kim et al., 2004). It hasrecently been demonstrated that HSP22 forms a complex with theco-chaperone Bag3 to target misfolded proteins to degradation bymacroautophagy (Carra et al., 2008a,b). In addition, HSP22possesses pro-apoptotic activity, in contrast to the anti-apoptoticactivity of most of the small HSPs (Gober et al., 2003; Li et al., 2007).In line with the fact that small HSPs form homo- and hetero-oligomeric complexes, HSP22 interacts with HSP27 (HSPB1), MKBP(HSPB2), HSPB3, aB-crystallin (HSPB5), HSP20 (HSPB6) and cvHSP(HSPB7) (Fontaine et al., 2005; Sun et al., 2004).

Although mutations of HSP22 are known to cause CMT2L andother neuromuscular disorders, the molecular mechanism under-lying these diseases is poorly understood (Irobi et al., 2004; Tanget al., 2005). These missense mutations, located in the central a-crystallin domain of HSP22, decrease the chaperone-like activityand alter the interaction with other small HSPs (Irobi et al., 2004;Kim et al., 2006). Interestingly, it has been shown that some HSP22mutants are less effective than the wild type protein in preventingHtt43Q aggregation, a pathogenic form of huntingtin responsiblefor Huntington’s disease (Carra et al., 2005). Huntingtin is aubiquitously expressed protein in mammals that has a role in theintracellular transport of vesicles and organelles along micro-tubules (Caviston and Holzbaur, 2009; DiFiglia et al., 1995; Hoffneret al., 2002). Huntingtin is also linked to actin-based andendosomal motility; however, its function is not yet fullyunderstood (Caviston and Holzbaur, 2009; Pal et al., 2006). Mutanthuntingtin causes defective axonal trafficking, and thus defects inhuntingtin protein clearance due to mutations in HSP22 mightaffect the intracellular trafficking along the axon. This may explainwhy HSP22 mutations specifically affect neurite length and motorneuron integrity without affecting other cell types (Gunawardenaet al., 2003; Irobi et al., 2010; Szebenyi et al., 2003; Trushina et al.,2004).

HSP27/HSPB1 is ubiquitously expressed in human tissues and,as mentioned above, interacts with HSP22 (Sun et al., 2004). HSP27is important for axonal outgrowth in the peripheral nervoussystem, and is induced in regenerated axons (Hirata et al., 2003;


Read and Gorman, 2009; Williams et al., 2005). HSP27 has a keyrole in neuronal survival, binding to molecular components of theapoptotic machinery to inhibit neuronal cell death (Benn et al.,2002; Voss et al., 2007). It also functions in proteasome-mediateddegradation of proteins. Indeed, HSP27 interacts with componentsof the proteasome and binds ubiquitin, facilitating proteindegradation (Parcellier et al., 2006, 2003).

Although HSP27 regulates cytoskeletal dynamics, the molecularmechanism is not fully understood. It is known that HSP27associates with and stabilizes the actin cytoskeleton (Jia et al.,2010; Pivovarova et al., 2007). HSP27 affects actin at the cellsurface, with effects on membrane ruffling, pinocytosis, cellmigration and accumulation of stress fibers (Doshi et al., 2009;Lavoie et al., 1993; Lee et al., 2008; Mounier and Arrigo, 2002;Schneider et al., 1998). Phosphorylation of HSP27 by MAPKpathways regulates actin polymerization, whereas unphosphory-lated HSP27 monomers inhibit actin polymerization (Benndorfet al., 1994; Guay et al., 1997; Kostenko et al., 2009; Pichon et al.,2004; Schneider et al., 1998). Blocking HSP27 phosphorylation indorsal root ganglion neurons by inhibition of MAPK pathwayscauses aberrant neurite growth, highlighting the importance ofphosphorylated-HSP27 for the interaction with actin and neuriteoutgrowth (Williams et al., 2005).

HSP27 also associates with intermediate filaments, preventingtheir aggregation (Jia et al., 2010; Perng et al., 1999). Interestingly,HSP27 mutants lead to progressive degeneration of motor neuronswhich disrupts the neurofilament network with consequentaggregation of NEFL protein, thus providing evidence for theessential role of HSP27 in neurofilament assembly (Evgrafov et al.,2004; Zhai et al., 2007). Importantly, mutations in the NEFL genealso cause a form of CMT2 (CMT2E) (Fabrizi et al., 2007a). Fourmissense mutations associated with distal hereditary motorneuropathy and CMT2F occur in the HSP27 conserved a-crystallindomain and one is positioned in the variable C-terminal part(Evgrafov et al., 2004). Like HSP22 mutations, HSP27 mutations inthe core a-crystallin domain also decrease its chaperone function.Interestingly, high levels of HSP27 have been detected inindividuals with neurodegenerative disorders characterized byaccumulation of improperly folded proteins, inclusion bodies orplaques in the nervous system such as ALS, Alzheimer’s,Parkinson’s and Alexander’s disease (Head et al., 1993; Renkaweket al., 1999; Shimura et al., 2004; Vleminckx et al., 2002). SmallHSPs facilitate the refolding or degradation of misfolded proteins,preventing their aggregation. Alterations in these functions couldtherefore explain the role of HSP27 in the progression of thesedisorders.

Given the diversity of the interactions and functions of the smallHSPs, the identification of the pathological mechanism responsiblefor the forms of CMT neuropathy caused by mutations in HSP22and HSP27 is not straightforward. These mutations could interferewith the chaperone-like activity, causing misfolding and aggrega-tion of other proteins. The fact that patients present CMTneuropathies late in life could be explained by the delayed effectsof aggregates accumulating in neurons. Another mechanism for thedisease may be that small HSP mutations alter the apoptoticpathway, thereby influencing the pro-survival activity of HSP27 orthe pro-apoptotic activity of HSP22. However, the role of HSP27 inneurofilament assembly and the disruption of the neurofilamentnetwork caused by HSP27 mutants strongly suggest that thepathologic mechanism for CMT2F is based on alterations ofcytoskeletal dynamics and axonal transport. HSP22 has not beenshown to interact with cytoskeletal elements; however, it ispossible that mutated HSP22 indirectly affects axonal transportthrough the interaction with its partner HSP27. In line with thishypothesis, it has been demonstrated that mutations in HSP22increase the interaction with HSP27, leading to the formation of




G Model


aggregates (Irobi et al., 2004). Thus, HSP22 mutations mightinterfere with HSP27 function. In conclusion, the mutations inHSP27 and HSP22, which cause two forms of CMT disease, couldalter, directly or indirectly, cytoskeletal functions and affect axonaltransport in motor and sensory neurons.

4.5.2. LRSAM1

A mutation of the LRSAM1 gene has recently been identified inpatients with an autosomal recessive axonal form of CMT disease(Guernsey et al., 2010). LRSAM1 (leucine rich repeat and sterilealpha motif 1), also known as TAL (Tsg101-associated ligase) orRIFLE, is a RING finger E3 ubiquitin ligase that plays a role inendocytosis and in adhesion of neuronal cells in culture (Amitet al., 2004; Li et al., 2003). Tsg101 (tumor susceptibility gene 101)sorts monoubiquitinated cargoes like EGFR into MVBs andretroviral Gag proteins for budding out of the cell (Bishop et al.,2002; Garrus et al., 2001; Katzmann et al., 2001; Slagsvold et al.,2006). LRSAM1 has two domains that independently bind toTsg101. Bivalent binding is essential for attachment of multiplemonomeric ubiquitins to Tsg101 (McDonald and Martin-Serrano,2008). Following ubiquitination, Tsg101’s sorting function isinactivated (Amit et al., 2004) (Fig. 3). A recycling model ofubiquitination/deubiquitination has been proposed wherebymultiple monoubiquitination of Tsg101 by LRSAM1 inactivatesTsg101 and deubiquitinating enzymes reactivate its sortingfunction, thus regulating its shuttling between a membrane-bound active form and an inactive soluble form (Amit et al., 2004).LRSAM1 is also a regulator of Tsg101 expression. Polyubiquitina-tion of Tsg101 C-terminal lysines by LRSAM1 targets excess of theprotein to proteasomal degradation (McDonald and Martin-Serrano, 2008). LRSAM1 mutations that make the protein catalyti-cally inactive and its depletion by siRNA both accelerate receptordegradation (Amit et al., 2004). It is interesting to note that theLRSAM1 gene mutation detected in patients with CMT neuropathyappears to be a loss-of-function of the gene product, suggestingthat the disease-causing mutation affects the degradative pathway(Guernsey et al., 2010).

4.5.3. LITAF/SIMPLE

The LITAF/SIMPLE gene was identified in 1997 as a p53-inducedgene, PIG7 (Polyak et al., 1997). LITAF/SIMPLE is a widely expressedgene encoding a protein involved in protein degradation that hasbeen proposed to localize to early endosomes (Lee et al., 2011b) orto the late endosomal/lysosomal compartments (Eaton et al., 2011;Moriwaki et al., 2001). LITAF/SIMPLE is a non-glycosylatedmembrane protein that exhibits patches of sequence similaritywith major integral membrane proteins of lysosomes, LAMPs,LIMPs, and also with endolyn, mainly in the N-terminal domain. ItsC-terminus contains a modified RING finger domain and thecarboxyl terminus signal for endocytosis YXXF (where F is anybulky hydrophobic amino acid) (Eaton et al., 2011; Lee et al.,2011b; Moriwaki et al., 2001). LITAF/SIMPLE contains two domainsat the N-terminus that mediate the interaction with WW domain-containing proteins: a PPXY responsible for binding to neuronalprecursor cell-expressed developmentally downregulated 4(Nedd4); and a P(S/T)AP motif that binds with Tsg101 (Shirket al., 2005). The same domains are also responsible for the bindingof another WW domain-containing protein, Itch (Eaton et al.,2011). Nedd4 is an E3 ubiquitin ligase which monoubiquitinatesmembrane proteins that need to reach the lysosomes in order to bedegraded (Ingham et al., 2004). ESCRT is the machinery involved inthe sorting of ubiquitinated membrane proteins to lysosomes.Monoubiquitinated substrates are recognized by Tsg101, acomponent of ESCRT-I that acts downstream of Nedd4 (Blotet al., 2004; Haglund et al., 2003). ESCRT-II and -III complexessubsequently sort target proteins into MVBs. Following fusion with


lysosomes, the MVB content is degraded (Raiborg and Stenmark,2009). Although the function of LITAF/SIMPLE is not yet fullycharacterized, the following hypothesis based on its interactionwith Nedd4 and Tsg101 and on its localization along the endo-lysosomal pathway currently exists: Nedd4 ubiquitinates LITAF/SIMPLE and the ubiquitinated LITAF/SIMPLE interacts with Tsg101,suggesting a role for LITAF/SIMPLE in the ubiquitin-mediatedlysosomal degradation pathway (Shirk et al., 2005) (Fig. 3).

Itch is a member of the Nedd4 family that ubiquitinates andinduces proteasomal degradation of different substrates (Azakirand Angers, 2009; Azakir et al., 2010; Chang et al., 2006; Rossi et al.,2005). It localizes to the TGN, but after the interaction with LITAF/SIMPLE, it changes its localization to lysosomes (Angers et al.,2004; Eaton et al., 2011). Even though Itch and Nedd4 are verysimilar proteins and members of a conserved family of ubiquitinligases, Nedd4 localization is not altered by LITAF/SIMPLE (Eatonet al., 2011).

Mutations of the LITAF/SIMPLE gene are associated with CMT1C,an autosomal dominant demyelinating form of CMT type 1,suggesting that LITAF/SIMPLE may have a critical role in peripheralnerve function (Bennett et al., 2004; Gerding et al., 2009; Latouret al., 2006; Saifi et al., 2005; Street et al., 2003). Despite theubiquitous pattern of expression, the high expression level ofLITAF/SIMPLE in the peripheral nerves and Schwann cells explainswhy mutations in this protein can cause a demyelinatingneuropathy that specifically affects the peripheral nervous system(Lee et al., 2011b; Moriwaki et al., 2001; Street et al., 2003).However, how these mutations cause peripheral nerve demyelin-ation is unknown. It has recently been shown that CMT1C-linkedmutants mislocalize from the membrane of early endosomes to thecytosol and that they are unstable, prone to aggregation, anddegraded by both the proteasome and aggresome–autophagypathways (Lee et al., 2011b). These findings, together with the factthat CMT1A (another form of CMT neuropathy caused by geneduplication or point mutations in PMP22) is also characterized bythe formation of intracellular ubiquitinated PMP22 aggregates(aggresomes), suggest protein misfolding as a common cause ofdemyelinating peripheral neuropathies and highlight the impor-tance of the proteasome and autophagy pathways in the clearanceof CMT disease-associated mutant proteins (Fortun et al., 2006;Ryan et al., 2002).

4.6. Defects in mitochondrial dynamics and mitochondrial axonal

transport: MFN2 and GDAP1

4.6.1. MFN2

Mitofusins mediate the process of mitochondrial fusion andregulate mitochondrial metabolism, apoptosis and cellular signal-ing (de Brito and Scorrano, 2008b; Santel, 2006). MFN2 isimportant not only for mitochondrial fusion but also for tetheringof mitochondrial and ER membranes (de Brito and Scorrano, 2008a,2010). MFN2 mutations are associated with type 2A of CMT diseaseand with hereditary motor and sensory neuropathy type VI (Kijimaet al., 2005; Lawson et al., 2005; Zuchner et al., 2006, 2004). Bothdisorders lead to axonal degeneration, and the latter is coupledwith visual impairment due to optic atrophy (Zuchner et al., 2006).MFN2 mutations in CMT2A are located in the GTPase domain and inthe C-terminal coiled-coil domain, suggesting that the mutatedproteins are defective either in GTPase activity or in the capacity totether to fusion partners during mitochondrial fusion (Santel,2006; Verhoeven et al., 2006). Interestingly, mutations in OPA1, amitochondrial inner membrane protein important for mitochon-drial fusion, also result in neuropathologies, suggesting thatalterations in the fusion process may be the cause of neuronaldisorders (Alexander et al., 2000). However, it is not clear whydefects in mitochondrial fusion would affect neuronal cells only.




G Model


The mechanism by which MFN2 mutations cause CMT2A isunknown. Current models propose that it could be the conse-quence of mitochondrial transport defects in the axons (Cartoniand Martinou, 2009). Mitochondrial transport and distribution areparticularly important for neurons, where energy is required farfrom the cell body, along axons and dendrites. In agreement withthis hypothesis that mutations in MFN2 may perturb the dynamicsor the axonal transport of mitochondria, expression of CMT2A-related MFN2 mutants in neurons leads to mitochondrial transportdefects and aggregation around the nucleus, with few and mostlystatic mitochondria along axons. Interestingly, the decrease ofaxonal mitochondrial transport is not caused by alterations inmitochondrial oxidative respiration, indicating that alterationscaused by CMT2A mutants are independent of defects in energyproduction (Baloh et al., 2007). In addition, mitochondria areimproperly distributed along the axon in motoneurons oftransgenic mice expressing an MFN2 pathogenic allele, and inPurkinje cells of MFN2-deficient mice (Chen et al., 2007; Detmeret al., 2008). It has been demonstrated that a correct mitochondrialdistribution in peripheral axons is also important for the properfunction of neurons in Drosophila (Guo et al., 2005; Stowers et al.,2002; Verstreken et al., 2005). Finally, in CMT2A patients,mitochondria accumulate in the distal part of sural nerve axons(Verhoeven et al., 2006).

Adaptor proteins connect mitochondria to kinesin and dyneinmotor proteins that are responsible for anterograde and retrogradetransport along axonal microtubules (Fransson et al., 2006; Glateret al., 2006; Hollenbeck and Saxton, 2005; Li et al., 2009). Alteredmitochondrial distribution is also seen in cells lacking the kinesinKif5b, and in cells transfected with mutated Miro adaptor protein(Fransson et al., 2006; Guo et al., 2005; Tanaka et al., 1998). Miro isa transmembrane GTPase, associated with the outer membrane ofmitochondria, important for the correct axonal transport ofmitochondria in neurons (Guo et al., 2005). It forms a complexwith Milton, that in turn binds to the kinesin heavy chain.Therefore, the Milton/Miro complex connects kinesins to mito-chondria (Fransson et al., 2006; Glater et al., 2006; Stowers et al.,2002). It was recently demonstrated that MFN2 interacts withmammalian Miro (Miro1/Miro2) and Milton (OIP106/GRIF1),regulating mitochondrial transport in axons (Misko et al., 2010).Taken together, these findings strongly indicate that defect(s) inmitochondrial axonal transport could be the underlying mecha-nism responsible for the pathophysiology of CMT2A.

4.6.2. GDAP1

More than 40 different mutations in ganglioside-induceddifferentiation-associated protein 1 (GDAP1) cause different formsof CMT neuropathy (Baxter et al., 2002; Cassereau et al., 2011;Cuesta et al., 2002). Mutations in the GDAP1 gene are usually linkedto recessive forms of CMT disease (CMT4A or AR CMT2) and morerarely to a dominant form (CMT2K), the latter being far less severe(Cassereau et al., 2011). Indeed, recessive forms of CMT neuropathydue to GDAP1 mutations show an early onset, usually in the firstdecade of life, and rapid progression of the disease with assistedwalking after the age of 10 and wheelchair requirement in the thirddecade of life (Cassereau et al., 2011). Missense mutations havebeen reported in sporadic cases of CMT disease (Kabzinska et al.,2011).

GDAP1 is highly expressed in neurons, in particular in motorand sensory neurons of the spinal cord, and it is localized to themitochondrial outer membrane (Niemann et al., 2005; Pedrolaet al., 2005). GDAP1 has a single transmembrane domain and itstargeting to the outer mitochondrial membrane and function aredependent on its tail anchor (Wagner et al., 2009). GDAP1 isimportant for mitochondrial network dynamics (Niemann et al.,2005; Pedrola et al., 2005). Indeed, silencing of GDAP1 results in


tubular mitochondrial morphology, whereas overexpression ofGDAP1 induces fragmentation of mitochondria (Pedrola et al.,2008). Interestingly, in the recessively inherited forms of CMTdisease, GDAP mutated proteins have reduced fission activities. Inthe dominantly inherited forms of CMT neuropathy, GDAPmutated proteins negatively influence the fusion of mitochondria(Niemann et al., 2009). Truncated GDAP, resulting from CMTdisease-causing mutations, is not targeted to mitochondria and isthus unable to cause mitochondrial fragmentation, inducingperturbation of normal mitochondrial dynamics (Niemann et al.,2005). Alterations of mitochondrial dynamics disturb the integrityof peripheral nerves, leading to both axonal and myelinationdefects (Niemann et al., 2005). However, CMT disease-associatedmutations in GDAP1 appear to lead mainly to an axonal phenotype,although a variable degree of demyelination has been observedassociated with the different mutations (Cassereau et al., 2011).Therefore, it is unclear whether GDAP1 mutations affect bothneurons and Schwann cells, and whether their effect is cell-autonomous or caused by altered axon-Schwann cell interactions(Suter and Scherer, 2003). As mitochondrial dynamics are affectedby GDAP1 mutations, it is believed that mitochondrial motility, inparticular in the more distal portion of the axons, could be affectedas well as energy production by mitochondria (Cassereau et al.,2011).

4.7. Defects in myelination

As demyelinating defects are one of the major causes of CMTneuropathy, mutations in a number of different genes involved inmyelination have been identified. The first two, PMP22 and MPZ,encode structural components of myelin. PMP22, a small proteinexpressed primarily in Schwann cells, is a major component of themyelin sheath. It is important for correct myelination andmaintenance of the myelin sheath and axons (Naef and Suter,1998; Snipes et al., 1992). Duplication, deletion or point mutationsof PMP22 are associated with different forms of CMT disease:CMT1A, Hereditary Neuropathy with liability to Pressure Palsies(HNPP), CMT1E and AR CMT1 (Dubourg et al., 2006; Houlden andReilly, 2006) (Table 1). Furthermore, the major integral membraneprotein of peripheral nerve myelin, MPZ (myelin protein zero), ismutated in CMT1B, AR CMT1 (Dejerine–Sottas neuropathy) andCMT2I/J (Berger et al., 2006b; Houlden and Reilly, 2006; Shy, 2006).MED25, also known as ARC92 or ACID1, is a component of theMediator complex that recruits RNA polymerase II to specific genepromoters (Rana et al., 2011). A mutation in MED25 leads toCMT2B2 (Leal et al., 2009). Patients present a classic axonalperipheral neuropathy with mild myelin defects (Leal et al., 2009).Data showing that MED25 expression levels correlate with PMP22expression levels suggest that one of the genes regulated byMED25 is PMP22, indicating that MED25 is important inmyelination (Leal et al., 2009).

Other genes involved in myelination and mutated in CMTdisease are early growth response 2 (EGR2), Gap junction b-1(GjB1) and periaxin (PRX). EGR2 is a zinc finger transcription factorthat induces the expression of several proteins involved in myelinsheath formation and maintenance, for example, MPZ (Jang andSvaren, 2009). Mutations of EGR2 have been shown to beassociated with CMT1D, CMT4E, Dejerine–Sottas neuropathyand congenital hypomyelinating neuropathy (Bellone et al.,1999; Mikesova et al., 2005; Timmerman et al., 1999; Warneret al., 1998; Yoshihara et al., 2001). Mutations of EGR2 causing CMTdisease inhibit myelin gene expression. It has been demonstratedthat one of these mutations decreases the binding of EGR2 to thepromoter of GjB1, another gene associated with CMT neuropathythat is important for myelination (Musso et al., 2001; Nagarajanet al., 2001). The GjB1 protein (also called connexin-32) is a




G Model


transmembrane protein that oligomerizes to form gap junctionchannels that allow diffusion of small molecules (Rahman et al.,1993). Altered function of this protein results in demyelination ascommunication between glial cells and neurons is disrupted(Abrams et al., 2002, 2003, 2001; Neuberg and Suter, 1999). GjB1mutation leads to a form of X-linked CMT disease (CMTX1)(Bergoffen et al., 1993; Fairweather et al., 1994; Ionasescu et al.,1994; Schiavone et al., 1996). PRX is a Schwann cell-specificprotein that has a role in axon–glial interactions and is expressed ina developmentally regulated manner (Gillespie et al., 1994;Scherer et al., 1995). PRX is important for the maintenance ofperipheral nerve myelin and, in particular, for ensheathingregenerating axons (Gillespie et al., 1994; Scherer et al., 1995).A mouse model lacking functional PRX exhibits morphologicalchanges in the neuromuscular junction. In particular, the terminalportion of peripheral motor axons shows extensive pre-terminalbranches in demyelinated regions and axonal swelling, associatedwith asynchronous failure of action potential transmission at highstimulation frequencies (Court et al., 2008). Mutations in PRXcause CMT4F and Dejerine–Sottas neuropathy (Boerkoel et al.,2001; Guilbot et al., 2001; Kabzinska et al., 2006; Kijima et al.,2004; Marchesi et al., 2010; Takashima et al., 2002).

4.8. Other defects: PRPS1 and ARHGEF10

Although more than 30 genes have been shown to be associatedwith different forms of CMT neuropathy, the disease-gene ofseveral forms has yet to be identified. Furthermore, the exactnature of the involvement of some identified disease-genes is stillunclear. For these genes, when possible, the putative molecularmechanisms underlying the disease are discussed.

4.8.1. PRPS1

Mutations in PRPS1 (phosphoribosylpyrophosphate synthetase1) cause a number of different syndromes, one of which is an X-linked form of CMT disease termed CMT5 or Rosenberg-Chutoriansyndrome (de Brouwer et al., 2010). Patients show peripheraldemyelination and axonal loss. PRS1 is an enzyme required fornucleotide biosynthesis. There are a number of hypothesesregarding how mutations in PRS1 can affect peripheral neurons(de Brouwer et al., 2010). One hypothesis is linked to the fact that formyelin biosynthesis, lipid esters of nucleotides are required as wellas S-adenosylmethionine as a co-factor (de Brouwer et al., 2010).Thus, mutations harming PRS1 would reduce the amount ofnucleotides, thereby affecting myelination. Another hypothesis isthat mutations would decrease the amount of GTP that is required bya number of proteins that regulate membrane traffic or cytoskeletaldynamics, as, for instance, Rab proteins, dynamins/dynamin-likeproteins and the Rho GTPase family of actin regulators (de Brouweret al., 2010). In this case, mutations in PRS1 would affect membranetraffic. However, there is currently no evidence for this hypothesisnor for other alternative hypotheses.

4.8.2. ARHGEF10

ARHGEF10 (Rho guanine nucleotide exchange factor 10) is aGEF for members of the Rho superfamily of small GTPases involvedin the regulation of the actin cytoskeleton (Mohl et al., 2006). Amutation in ARHGEF10 causes a mild dominant intermediate formof CMT disease, characterized by slowed nerve conductionvelocities and thin myelination (Verhoeven et al., 2003b). Thephenotype is not progressive, suggesting that ARHGEF10 isinvolved in myelination during development (Verhoeven et al.,2003b). ARHGEF10 is thus a regulator of the actin cytoskeleton, andalthough there is no evidence supporting this hypothesis,mutations in ARHGEF10 could alter actin-dependent membranetraffic events.


4.9. Defects not directly related to trafficking: aminoacyl-tRNA

synthetases, LMNA, BSCL2, TRPV4, CTDP1 and HK1

4.9.1. Aminoacyl-tRNA synthetases

Mutations in glycyl-, tyrosyl- and alanyl-tRNA synthetases(GARS, YARS and AARS) cause the autosomal dominant CMT2D, DI-CMTC and CMT2M forms, respectively (Antonellis et al., 2003;Jordanova et al., 2006; Latour et al., 2010). Aminoacyl-tRNAsynthetases (ARS) catalyze the transfer of amino acids onto theappropriate tRNA during translation. Mutations of tRNA synthe-tases cause neurodegeneration and are responsible for otherneurological diseases such as spinal cord disorders, leukoence-phalopathy and distal spinal muscular atrophy (Antonellis andGreen, 2008; Edvardson et al., 2007). The fact that peripheralneurons are affected in a cell-autonomous manner indicates thatthis type of neuron is more sensitive to protein translation defects.Although the mechanism by which mutations in these genes causeperipheral neuropathies is unknown, several hypotheses havebeen put forward (Antonellis and Green, 2008). The mutationscould affect the ability of the enzymes to charge the amino acids ontRNAs or could alter their intracellular localization (Antonellis andGreen, 2008). However, a recent study utilizing mouse modelsestablished that mutations in ARS do not cause peripheralneuropathies through amino acid mischarging or through a defectin their known functions in translation (Antonellis and Green,2008; Stum et al., 2011). This suggests that the mutations couldaffect RNA charging occurring specifically in axons, leading toneurodegeneration (Antonellis and Green, 2008; Stum et al., 2011).Alternatively, the mutations could affect non-canonical functionsof ARS. In this respect, it is worth noting that ARS possessadditional functions not directly related to their canonicalfunction. For example, some ARS are involved in transcriptionsilencing, inflammatory responses, signaling or apoptosis (Anto-nellis and Green, 2008; Park et al., 2005, 2009).

4.9.2. LMNA

The LMNA gene encodes the lamin A/C nuclear envelope proteinand is mutated in CMT2B1 and a number of other diseases,including Emery–Dreifuss muscular dystrophy and cardiomyopa-thy (Bonne et al., 1999; De Sandre-Giovannoli et al., 2002; Fatkinet al., 1999; Worman et al., 2010). Lamins are intermediatefilament proteins that form the nuclear lamina, which provides thenuclear envelope and nuclear components with structural support.They are important for DNA replication, gene expression, nucleartransport, apoptosis and signaling (Hutchison and Worman, 2004).The A-type lamins are important in the protection of the cell frommechanical damage. Thus, mutations in LMNA could negativelyinfluence this protection, leading to neuronal (axonal) degenera-tion (Hutchison and Worman, 2004; Niemann et al., 2006).

4.9.3. BSCL2

BSCL2 (Berardinelli-Seip congenital lipodystrophy 2) protein,also called seipin, has been found mutated in autosomal dominantaxonal CMT2D and Silver syndrome, as well as in a number of otherdisorders including spastic paraplegia (Ito and Suzuki, 2009;Windpassinger et al., 2004). Seipin is a transmembrane proteinlocalized to the ER and degraded by the ubiquitin–proteasomesystem (Ito and Suzuki, 2009; Windpassinger et al., 2004). Mutantsof seipin induce ER stress-mediated cell death, suggesting that ERstress could be the cause of neurodegeneration (Ito and Suzuki,2009). Seipin is known to regulate adipocyte differentiation, lipiddroplet formation and motor neuron development (Fei et al.,2011). Furthermore, seipin mutants induce the formation ofaggregates that could lead to degeneration (Ito and Suzuki, 2009;Windpassinger et al., 2004). The exact roles of seipin and of itsdisease-causing mutants remain to be elucidated.




G Model


4.9.4. TRPV4

TRPV4 (transient receptor potential cation channel subfamily Vmember 4) is a member of the TRP superfamily of cation channels.Mutations in the TRPV4 gene cause CMT2C, skeletal dysplasia andscapuloperoneal muscular atrophy (Deng et al., 2010; Landoureet al., 2010). TRPV4 plays a key role in osmosensation, temperaturesensation and mechanosensation (Kottgen et al., 2008). AlthoughTRPV4 is poorly expressed in neurons, alterations of this proteinare highly toxic in neuronal cells, causing important changes incalcium concentrations. Thus, several neuronal processes, such asneurite outgrowth and synaptic transmission, are affected, leadingto neurodegeneration (Deng et al., 2010; Landoure et al., 2010).

4.9.5. CTDP1

A mutation in the CTDP1 (C-terminal domain phosphatase 1)gene causes congenital cataracts facial dysmorphism neuropathysyndrome (CCFDN) (Varon et al., 2003). One of the symptomspatients show is hypomyelination of peripheral nerves. The CTDP1

gene encodes the protein phosphatase FCP1, which is a componentof the transcription machinery. The CCFDN-associated mutationaffects a nucleotide in intron 6 causing aberrant splicing (Varonet al., 2003). FCP1 dephosphorylates a serine in the C-terminaldomain of the largest RNA polymerase II subunit, regulating geneexpression (Varon et al., 2003). It is not known why a mutation inFCP1 causes CCFDN. It is possible that defects in the expression ofspecific genes could cause this neuropathy, or alternatively themutation could impair unknown functions of FCP1.

4.9.6. HK1

HK1 (hexokinase 1) is mutated in CMT4G (also referred to ashereditary motor and sensory neuropathy-Russe, HMSNR) (Hantkeet al., 2009). Hexokinases are sugar kinases that catalyze thephosphorylation of glucose, the first step in glucose metabolism.HK1 binds to mitochondria and it is the major regulator of theproduction of ATP by the cell’s energy metabolism (Wilson, 2003).On mitochondria, HK1 is also involved in the regulation of cellsurvival. Mutations in HK1 cause hexokinase deficiency and severenonspherocytic hemolytic anemia (Hantke et al., 2009). Interest-ingly, HK1 is highly expressed in the nervous system, in particularat the level of dorsal root ganglia, and it is involved in

Table 2Functions affected by CMT disease-associated mutations.

Function Protein

Regulation of membrane trafficking: vesicle fission DNM2 (also regulat

actin cytoskeleton)

Regulation of membrane trafficking:

polyphosphoinositide phosphatases

MTMR2

MTMR13

FIG4

Cytoskeletal transport

Regulation of cytoskeletal organization and maintenance

KIF1BbNEFL

FGD4/Frabin

Regulation of membrane trafficking: endosomal maturation Rab7 (also regulate

protein degradation

Regulation of membrane trafficking: endosomal recycling NDRG1

SH3TC2

Regulation of protein degradation: chaperone-like activity HSP22/HSPB8

HSP27/HSPB1

(also regulates

actin cytoskeleton)

Regulation of protein degradation: ubiquitin ligase LRSAM1

Regulation of protein degradation: ubiquitin-

mediated lysosomal degradation pathway

LITAF/SIMPLE

Regulation of mitochondrial dynamics

and mitochondrial axonal transport

MFN2

GDAP1


NGF-mediated neurite outgrowth (Hantke et al., 2009). Themolecular mechanism underlying CMT4G is currently unknown;however, it could involve alterations of apoptotic activity oralterations of unknown alternative functions of HK1 specific for theperipheral nervous system (Hantke et al., 2009).

5. Conclusions and future directions

Several neuropathies are caused by functional alterations ofintracellular traffic proteins. We have reviewed here the knowngenetic causes of CMT neuropathy, highlighting genes withfunctions related, directly or indirectly, to intracellular trafficking.Interestingly, many CMT disease-associated mutations alter genesinvolved in the regulation of the endomembrane system, stronglysuggesting ‘problems in intracellular trafficking’ to be a majorcause of CMT neuropathy (Fig. 4). Although each gene has morethan one role in the cell, these genes can be grouped on the basis ofthe function most likely to be altered and, thus, most likely toconstitute the basis of the molecular mechanism of actionunderlying the neuropathy (Table 2). CMT disease-associatedmutations in the proteins indicated in Table 2 alter the regulationof PI metabolism, cytoskeletal organization and transport,endosomal trafficking, protein degradation, mitochondrial dynam-ics and mitochondrial axonal transport (Table 2; Fig. 4). However,other CMT disease-associated proteins could also be involved inthe regulation of membrane traffic, although indirectly. Forexample, defects in PRS1 could alter the availability of nucleotidesand thus affect the Rab and/or Rho GTPase cycle, impairingmembrane traffic or cytoskeleton organization. Altered ARHGEF10function could affect the regulation of the actin cytoskeleton andthus, indirectly, trafficking. To date, more than 40 different geneshave been linked to CMT neuropathy. In the near future, due to theintroduction of next generation sequencing systems, it is verylikely that many other genes – which may be mutated in only a fewindividuals – will be identified.

It is puzzling that, despite the large variety of genes involved,some of which are even ubiquitous, all patients with CMTneuropathy show similar and specific defects, mainly limited toperipheral motor and sensory neurons. As alterations in a numberof different genes lead to similar phenotypes in CMT disease

Domains Interactors

es GTPase, MD, PH, GED, PRD Abp1, amphiphysins, CIN85,

cortactin, g-tubulin, microtubules,

Rab7, SNX9, syndapin 2

PH-GRAM, PTP, CC, PDZ-BD

PH-GRAM, PTP, CC, PDZ-BD,

DENN, PH

SAC1

Dlg1, MTMR13, MTMR5, NEFL,

PSD-95, Vps34/Vps15

MTMR2

ArPIKfyve, PIKfyve

PH

Head, Rod, Tail

FYVE, PH, FAB, DH

DENN/MADD

MTMR2

Actin

s

)

GTPase FYCO1, PRA1, retromer, RILP,

TrkA, Vps34/Vps15

a/b hydrolase

SH3, TPR

APOA1, APOA2, E-cadherin/catenin,

PRA1, Rab4a

Rab11

a-Crystallin

a-Crystallin

aB-crystallin, Bag3, cvHSP, HSPB3,

HSP20, HSP27, MKBP

Actin, HSP22, intermediate filaments

LRRs, CC, ERM, SAM, RF, PTAP Tsg101

RF, PPXY, P(S/T)AP Itch, Nedd4, Tsg101

GTPase, CC

GST

Miro/Milton




G Model


patients, we hypothesize that defects in the potential to regenerateaxons following injury could be responsible for the different formsof CMT neuropathy. In this respect it is worth noting that, incontrast to peripheral neurons, neurons in the adult CNS do notregenerate their axons following injury (Huebner and Strittmatter,2009). Thus, all the genes causing CMT disease could be importantregulators of axonal regeneration, explaining why mainly periph-eral neurons are affected when the mutated gene encodes aubiquitous protein. Indeed, ubiquitous proteins may have aspecific additional role in the regeneration of axons or in otherneuronal-specific processes. In addition, the large variety of genesinvolved in the disease could be a reflection of the fact that axonalregeneration is a very complex process under the control of anumber of other cellular processes. First of all, axonal maintenanceand regeneration depend heavily on both myelinating and non-myelinating Schwann cells that respond to a number of differentneurotrophic factors which signal to transcription factors(Bhatheja and Field, 2006). Thus, alterations of Schwann cellfunction are responsible for a number of neuronal disorders,including CMT neuropathy. A number of different signal transduc-tion pathways, initiated mainly by neurotrophic factors and actingnot only on Schwann cells but also directly on neurons, areresponsible for the correct maintenance and regeneration of axons(Cui, 2006; Tucker and Mearow, 2008). Peripheral neurons arecapable of spontaneous axon regeneration, but this property isstrictly reliant on signaling pathways (Cui, 2006; Tucker andMearow, 2008). Signaling pathways control a number of otherimportant cellular processes, such as autophagy, neurite out-growth and membrane traffic, that influence greatly the ability ofthe axon to regenerate.

Defects identified in CMT disease include dysregulation of PIs(see Section 4.2), Rab7 (see Section 4.4.1) and HSP22 (see Section4.5.1), molecules that are involved in the regulation of theautophagy process. Autophagy dysfunction contributes to variousneurodegenerative disorders, as both defective and excessiveautophagy lead to neurite degeneration and neuronal atrophy(Garcıa-Arencibia et al., 2010; Gumy et al., 2010; Rubinsztein et al.,2005; Tooze and Schiavo, 2008). In particular, autophagy appearsto be important for axonal maintenance and regeneration. Inaddition, neurons present a constitutive autophagy process thatshows peculiar features and, possibly, molecular mechanisms notcommon to other cell types (Komatsu et al., 2007; Yue et al., 2008).Thus, alterations of neuronal-specific autophagy events couldexplain the clinical features of CMT disease patients, consideringalso that axonal regeneration occurs mainly in the peripheralnervous system (Huebner and Strittmatter, 2009).

DNM (see Section 4.1), Rab7 (see Section 4.4.1), HSP22 andHSP27 (see Section 4.5.1), TRPV4 (see Section 4.9.4) and HK1 (seeSection 4.9.6) are involved in the control of neurite outgrowth andare mutated in CMT neuropathy. Alterations of neurite outgrowthimpair efficient axonal regeneration (Raivich and Makwana, 2007;Rishal and Fainzilber, 2010). Neurite outgrowth occurs mainlyduring development; however, development is not impaired inCMT disease patients. Thus, we hypothesize that defective neuriteoutgrowth specifically affects axonal regeneration of peripheralnerves in CMT disease patients. How can this be explained? Defectsaffecting axonal development and regeneration in CMT diseasepatients are initially efficiently counteracted by other factors thatbecome less effective with age. Indeed, it is known that olderanimals are less successful in axonal regeneration, although themolecular bases for these changes are not yet understood (Hilliard,2009; Perlson et al., 2004; Wu et al., 2007). The age-related declinein the capacity of peripheral neurons to regenerate their axons dueto defects in neurite outgrowth may not be strong enough to havean effect on development, thus explaining why CMT disease-causing mutations affect mainly peripheral neurons and why the


onset of CMT neuropathy is often in the second to third decade oflife.

Axon repair, axon growth and axon regeneration are processesthat are dynamically dependent on cytoskeletal reorganization andintracellular trafficking events (Bloom and Morgan, 2011). Forcorrect axon regeneration, it is important to maintain axonpolarity, to initiate growth cone formation, and to promoteoutgrowth and correct synapse formation. All these steps requireiterative events of endocytosis and exocytosis and extensivecytoskeletal reorganization (Bloom and Morgan, 2011). Thus, theCMT disease-causing proteins involved in intracellular traffickingand cytoskeletal organization (Table 2; Fig. 4) could affect axonalregeneration by affecting one or more intracellular traffickingevents necessary for this process.

In the near future, we expect to see an increase in the number ofidentified genes that cause CMT neuropathy. It will be interestingto establish whether other intracellular traffic genes will beidentified as causative of CMT disease. It will be important toinvestigate, at the molecular level, the mechanism by which eachgene contributes to the disease in order to start to identify possibletherapeutic agents. In this respect, it will be valuable to continue toindividuate the genes whose defects affect primarily Schwann orneuronal cell function in order to identify the correct target.

The limited knowledge on the molecular mechanism underly-ing the different forms of the disorder is a consequence of a lack ofanimal models. Clearly, the availability of mouse, rat or monkeymodels would greatly contribute to our knowledge of the disease.However, we should also consider using simpler models that couldgenerate rapid and straightforward answers. For instance, as hasbeen the case for other disorders, the use of Drosophila models or,even better, the vertebrate zebrafish could help identify the exactrole in the disease of known genes with multiple cellular functions.

The complexity of the endomembrane system together with themultitude of mutated genes that are causative factors for CMTneuropathy makes it difficult to envisage a common cure/intervention of the disease process. However, further dissectionof the molecular mechanism of action of every single geneinvolved, together with a better general understanding ofintracellular trafficking in neurons and an improved knowledgeon how alterations of intracellular trafficking specifically affectperipheral neurons should open up a way for the development ofspecific therapeutic strategies against specific CMT disease targets.

Conflict of interest

The authors have no conflict of interest.

Acknowledgments

We thank Pietro Alifano for critical reading of the manuscript.Work in the authors’ laboratories has been partially supported byTelethon-Italy (grant no. GGP09045 to C.B.), by AIRC (AssociazioneItaliana per la Ricerca sul Cancro, Investigator grant no. 10213 toC.B.), by MIUR (Ministero dell’Istruzione, dell’Universita e dellaRicerca, ex60% to C.B.) and by NRC (Norwegian Research Council toC.P. and O.B.).

References

Abe, A., Numakura, C., Saito, K., Koide, H., Oka, N., Honma, A., Kishikawa, Y.,Hayasaka, K., 2009. Neurofilament light chain polypeptide gene mutations inCharcot–Marie–Tooth disease: nonsense mutation probably causes a recessivephenotype. J. Hum. Genet. 54, 94–97.

Abrams, C.K., Bennett, M.V., Verselis, V.K., Bargiello, T.A., 2002. Voltage opensunopposed gap junction hemichannels formed by a connexin 32 mutantassociated with X-linked Charcot–Marie–Tooth disease. Proc. Natl. Acad. Sci.U.S.A. 99, 3980–3984.




G Model


Abrams, C.K., Freidin, M., Bukauskas, F., Dobrenis, K., Bargiello, T.A., Verselis, V.K.,Bennett, M.V., Chen, L., Sahenk, Z., 2003. Pathogenesis of X-linked Charcot–Marie–Tooth disease: differential effects of two mutations in connexin 32. J.Neurosci. 23, 10548–10558.

Abrams, C.K., Freidin, M.M., Verselis, V.K., Bennett, M.V., Bargiello, T.A., 2001.Functional alterations in gap junction channels formed by mutant forms ofconnexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot–Marie–Tooth disease. Brain Res. 900, 9–25.

Ackerley, S., James, P.A., Kalli, A., French, S., Davies, K.E., Talbot, K., 2006. A mutationin the small heat-shock protein HSPB1 leading to distal hereditary motorneuronopathy disrupts neurofilament assembly and the axonal transport ofspecific cellular cargoes. Hum. Mol. Genet. 15, 347–354.

Aguilar, R.C., Wendland, B., 2003. Ubiquitin: not just for proteasomes anymore.Curr. Opin. Cell Biol. 15, 184–190.

Aidaralieva, N.J., Kamino, K., Kimura, R., Yamamoto, M., Morihara, T., Kazui, H.,Hashimoto, R., Tanaka, T., Kudo, T., Kida, T., Okuda, J., Uema, T., Yamagata, H.,Miki, T., Akatsu, H., Kosaka, K., Takeda, M., 2008. Dynamin 2 gene is a novelsusceptibility gene for late-onset Alzheimer disease in non-APOE-epsilon4carriers. J. Hum. Genet. 53, 296–302.

Alexander, C., Votruba, M., Pesch, U.E., Thiselton, D.L., Mayer, S., Moore, A., Rodri-guez, M., Kellner, U., Leo-Kottler, B., Auburger, G., Bhattacharya, S.S., Wissinger,B., 2000. OPA1, encoding a dynamin-related GTPase, is mutated in autosomaldominant optic atrophy linked to chromosome 3q28. Nat. Genet. 26, 211–215.

Aligianis, I., Johnson, C., Gissen, P., Chen, D., Hampshire, D., Hoffmann, K., Maina, E.,Morgan, N., Tee, L., Morton, J., Ainsworth, J., Horn, D., Rosser, E., Cole, T., Stolte-Dijkstra, I., Fieggen, K., Clayton-Smith, J., Megarbane, A., Shield, J., Newbury-Ecob, R., Dobyns, W., Graham, J.J., Kjaer, K., Warburg, M., Bond, J., Trembath, R.,Harris, L., Takai, Y., Mundlos, S., Tannahill, D., Woods, C., Maher, E., 2005.Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome.Nat. Genet. 37, 221–223.

Aligianis, I., Morgan, N., Mione, M., Johnson, C., Rosser, E., Hennekam, R., Adams, G.,Trembath, R., Pilz, D., Stoodley, N., Moore, A., Wilson, S., Maher, E., 2006.Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunitin a kindred with Martsolf syndrome. Am. J. Hum. Genet. 78, 702–707.

Allaire, P.D., Marat, A.L., Dall’Armi, C., Di Paolo, G., McPherson, P.S., Ritter, B., 2010.The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exitfrom early endosomes. Mol. Cell 37, 370–382.

Alto, N.M., Soderling, J., Scott, J.D., 2002. Rab32 is an A-kinase anchoring protein andparticipates in mitochondrial dynamics. J. Cell Biol. 158, 659–668.

Amit, I., Yakir, L., Katz, M., Zwang, Y., Marmor, M.D., Citri, A., Shtiegman, K., Alroy, I.,Tuvia, S., Reiss, Y., Roubini, E., Cohen, M., Wides, R., Bacharach, E., Schubert, U.,Yarden, Y., 2004. Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptorendocytosis and retrovirus budding. Genes Dev. 18, 1737–1752.

Angers, A., Ramjaun, A.R., McPherson, P.S., 2004. The HECT domain ligase itchubiquitinates endophilin and localizes to the trans-Golgi network and endo-somal system. J. Biol. Chem. 279, 11471–11479.

Aniento, F., Emans, N., Griffiths, G., Gruenberg, J., 1993. Cytoplasmic dynein-depen-dent vesicular transport from early to late endosomes. J. Cell Biol. 123, 1373–1387.

Anitei, M., Pfeiffer, S.E., 2006. Myelin biogenesis: sorting out protein trafficking.Curr. Biol. 16, R418–R421.

Antonellis, A., Ellsworth, R.E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.Q.,Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L.T., Sivakumar, K.,Ionasescu, V., Funalot, B., Vance, J.M., Goldfarb, L.G., Fischbeck, K.H., Green, E.D.,2003. Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299.

Antonellis, A., Green, E.D., 2008. The role of aminoacyl-tRNA synthetases in geneticdiseases. Annu. Rev. Genomics Hum. Genet. 9, 87–107.

Arnaud, E., Zenker, J., de Preux Charles, A.S., Stendel, C., Roos, A., Medard, J.J., Tricaud,N., Kleine, H., Luscher, B., Weis, J., Suter, U., Senderek, J., Chrast, R., 2009.SH3TC2/KIAA1985 protein is required for proper myelination and the integrityof the node of Ranvier in the peripheral nervous system. Proc. Natl. Acad. Sci.U.S.A. 106, 17528–17533.

Arneson, L.N., Segovis, C.M., Gomez, T.S., Schoon, R.A., Dick, C.J., Lou, Z., Billadeau,D.D., Leibson, P.J., 2008. Dynamin 2 regulates granule exocytosis during NK cell-mediated cytotoxicity. J. Immunol. 181, 6995–7001.

Arrigo, A.P., 2005. In search of the molecular mechanism by which small stressproteins counteract apoptosis during cellular differentiation. J. Cell. Biochem.94, 241–246.

Azakir, B.A., Angers, A., 2009. Reciprocal regulation of the ubiquitin ligase Itch andthe epidermal growth factor receptor signaling. Cell. Signal. 21, 1326–1336.

Azakir, B.A., Desrochers, G., Angers, A., 2010. The ubiquitin ligase Itch mediates theantiapoptotic activity of epidermal growth factor by promoting the ubiquityla-tion and degradation of the truncated C-terminal portion of Bid. FEBS J. 277,1319–1330.

Azzedine, H., Bolino, A., Taieb, T., Birouk, N., Di Duca, M., Bouhouche, A., Benamou, S.,Mrabet, A., Hammadouche, T., Chkili, T., Gouider, R., Ravazzolo, R., Brice, A.,Laporte, J., LeGuern, E., 2003. Mutations in MTMR13, a new pseudophosphatasehomologue of MTMR2 and Sbf1, in two families with an autosomal recessivedemyelinating form of Charcot–Marie–Tooth disease associated with early-onset glaucoma. Am. J. Hum. Genet. 72, 1141–1153.

Azzedine, H., Ravise, N., Verny, C., Gabreels-Festen, A., Lammens, M., Grid, D., Vallat,J.M., Durosier, G., Senderek, J., Nouioua, S., Hamadouche, T., Bouhouche, A.,Guilbot, A., Stendel, C., Ruberg, M., Brice, A., Birouk, N., Dubourg, O., Tazir, M.,


LeGuern, E., 2006. Spine deformities in Charcot–Marie–Tooth 4C caused bySH3TC2 gene mutations. Neurology 67, 602–606.

Baldassarre, M., Pompeo, A., Beznoussenko, G., Castaldi, C., Cortellino, S., McNiven,M.A., Luini, A., Buccione, R., 2003. Dynamin participates in focal extracellularmatrix degradation by invasive cells. Mol. Biol. Cell 14, 1074–1084.

Balla, T., 2005. Inositol-lipid binding motifs: signal integrators through protein–lipid and protein–protein interactions. J. Cell Sci. 118, 2093–2104.

Baloh, R.H., 2008. Mitochondrial dynamics and peripheral neuropathy. Neurosci-entist 14, 12–18.

Baloh, R.H., Schmidt, R.E., Pestronk, A., Milbrandt, J., 2007. Altered axonal mito-chondrial transport in the pathogenesis of Charcot–Marie–Tooth disease frommitofusin 2 mutations. J. Neurosci. 27, 422–430.

Banchs, I., Casasnovas, C., Albertı, A., De Jorge, L., Povedano, M., Montero, J.,Martınez-Matos, J.A., Volpini, V., 2009. Diagnosis of Charcot–Marie–Toothdisease. J. Biomed. Biotechnol. 2009, 985415.

Bandyopadhyay, S., Wang, Y., Zhan, R., Pai, S.K., Watabe, M., Iiizumi, M., Furuta, E.,Mohinta, S., Liu, W., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Takano, Y., Saito,K., Commes, T., Piquemal, D., Hai, T., Watabe, K., 2006. The tumor metastasissuppressor gene Drg-1 down-regulates the expression of activating transcrip-tion factor 3 in prostate cancer. Cancer Res. 66, 11983–11990.

Barisic, N., Claeys, K.G., Sirotkovic-Skerlev, M., Lofgren, A., Nelis, E., De Jonghe, P.,Timmerman, V., 2008. Charcot–Marie–Tooth disease: a clinico-genetic confron-tation. Ann. Hum. Genet. 72, 416–441.

Baron, W., Hoekstra, D., 2010. On the biogenesis of myelin membranes: sorting,trafficking and cell polarity. FEBS Lett. 584, 1760–1770.

BasuRay, S., Mukherjee, S., Romero, E., Wilson, M.C., Wandinger-Ness, A., 2010. Rab7mutants associated with Charcot–Marie–Tooth disease exhibit enhanced NGF-stimulated signaling. PLoS ONE 5, e15351.

Baxter, R.V., Ben Othmane, K., Rochelle, J.M., Stajich, J.E., Hulette, C., Dew-Knight, S.,Hentati, F., Ben Hamida, M., Bel, S., Stenger, J.E., Gilbert, J.R., Pericak-Vance, M.A.,Vance, J.M., 2002. Ganglioside-induced differentiation-associated protein-1 ismutant in Charcot–Marie–Tooth disease type 4A/8q21. Nat. Genet. 30, 21–22.

Bedford, L., Hay, D., Devoy, A., Paine, S., Powe, D.G., Seth, R., Gray, T., Topham, I., Fone,K., Rezvani, N., Mee, M., Soane, T., Layfield, R., Sheppard, P.W., Ebendal, T.,Usoskin, D., Lowe, J., Mayer, R.J., 2008. Depletion of 26S proteasomes in mousebrain neurons causes neurodegeneration and Lewy-like inclusions resemblinghuman pale bodies. J. Neurosci. 28, 8189–8198.

Begley, M.J., Taylor, G.S., Kim, S.A., Veine, D.M., Dixon, J.E., Stuckey, J.A., 2003. Crystalstructure of a phosphoinositide phosphatase, MTMR2: insights into myotubularmyopathy and Charcot–Marie–Tooth syndrome. Mol. Cell 12, 1391–1402.

Bellone, E., Di Maria, E., Soriani, S., Varese, A., Doria, L.L., Ajmar, F., Mandich, P., 1999.A novel mutation (D305V) in the early growth response 2 gene is associatedwith severe Charcot–Marie–Tooth type 1 disease. Hum. Mutat. 14, 353–354.

Benn, S.C., Perrelet, D., Kato, A.C., Scholz, J., Decosterd, I., Mannion, R.J., Bakowska,J.C., Woolf, C.J., 2002. Hsp27 upregulation and phosphorylation is required forinjured sensory and motor neuron survival. Neuron 36, 45–56.

Benndorf, R., Hayess, K., Ryazantsev, S., Wieske, M., Behlke, J., Lutsch, G., 1994.Phosphorylation and supramolecular organization of murine small heat shockprotein HSP25 abolish its actin polymerization-inhibiting activity. J. Biol. Chem.269, 20780–20784.

Bennett, C.L., Shirk, A.J., Huynh, H.M., Street, V.A., Nelis, E., Van Maldergem, L., DeJonghe, P., Jordanova, A., Guergueltcheva, V., Tournev, I., Van den Bergh, P.,Seeman, P., Mazanec, R., Prochazka, T., Kremensky, I., Haberlova, J., Weiss, M.D.,Timmerman, V., Bird, T.D., Chance, P.F., 2004. SIMPLE mutation in demyelinat-ing neuropathy and distribution in sciatic nerve. Ann. Neurol. 55, 713–720.

Berciano, J., 2011. Peripheral neuropathies: Molecular diagnosis of Charcot–Marie–Tooth disease. Nat. Rev. Neurol. 7, 305–306.

Berger, P., Berger, I., Schaffitzel, C., Tersar, K., Volkmer, B., Suter, U., 2006a. Multi-level regulation of myotubularin-related protein-2 phosphatase activity bymyotubularin-related protein-13/set-binding factor-2. Hum. Mol. Genet. 15,569–579.

Berger, P., Niemann, A., Suter, U., 2006b. Schwann cells and the pathogenesis ofinherited motor and sensory neuropathies (Charcot–Marie–Tooth disease). Glia54, 243–257.

Berger, P., Bonneick, S., Willi, S., Wymann, M., Suter, U., 2002. Loss of phosphataseactivity in myotubularin-related protein 2 is associated with Charcot–Marie–Tooth disease type 4B1. Hum. Mol. Genet. 11, 1569–1579.

Berger, P., Schaffitzel, C., Berger, I., Ban, N., Suter, U., 2003. Membrane association ofmyotubularin-related protein 2 is mediated by a pleckstrin homology-GRAMdomain and a coiled-coil dimerization module. Proc. Natl. Acad. Sci. U.S.A. 100,12177–12182.

Berger, P., Sirkowski, E.E., Scherer, S.S., Suter, U., 2004. Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cellsare the primary disease target in hereditary motor and sensory neuropathy-Lom. Neurobiol. Dis. 17, 290–299.

Bergoffen, J., Scherer, S.S., Wang, S., Scott, M.O., Bone, L.J., Paul, D.L., Chen, K., Lensch,M.W., Chance, P.F., Fischbeck, K.H., 1993. Connexin mutations in X-linkedCharcot–Marie–Tooth disease. Science 262, 2039–2042.

Bhatheja, K., Field, J., 2006. Schwann cells: origins and role in axonal maintenanceand regeneration. Int. J. Biochem. Cell Biol. 38, 1995–1999.

Bishop, N., Horman, A., Woodman, P., 2002. Mammalian class E vps proteinsrecognize ubiquitin and act in the removal of endosomal protein–ubiquitinconjugates. J. Cell Biol. 157, 91–102.

Bitoun, M., Durieux, A.C., Prudhon, B., Bevilacqua, J.A., Herledan, A., Sakanyan, V.,Urtizberea, A., Cartier, L., Romero, N.B., Guicheney, P., 2009. Dynamin 2 mutations




G Model


associated with human diseases impair clathrin-mediated receptor endocytosis.Hum. Mutat. 30, 1419–1427.

Bitoun, M., Maugenre, S., Jeannet, P.Y., Lacene, E., Ferrer, X., Laforet, P., Martin, J.J.,Laporte, J., Lochmuller, H., Beggs, A.H., Fardeau, M., Eymard, B., Romero, N.B.,Guicheney, P., 2005. Mutations in dynamin 2 cause dominant centronuclearmyopathy. Nat. Genet. 37, 1207–1209.

Bitoun, M., Stojkovic, T., Prudhon, B., Maurage, C.A., Latour, P., Vermersch, P.,Guicheney, P., 2008. A novel mutation in the dynamin 2 gene in a Charcot–Marie-Tooth type 2 patient: clinical and pathological findings. Neuromuscul.Disord. 18, 334–338.

Blatch, G.L., Lassle, M., 1999. The tetratricopeptide repeat: a structural motifmediating protein–protein interactions. Bioessays 21, 932–939.

Bloom, O.E., Morgan, J.R., 2011. Membrane trafficking events underlying axonrepair, growth, and regeneration. Mol. Cell. Neurosci. 48, 339–348.

Blot, V., Perugi, F., Gay, B., Prevost, M.C., Briant, L., Tangy, F., Abriel, H., Staub, O.,Dokhelar, M.C., Pique, C., 2004. Nedd4.1-mediated ubiquitination and subse-quent recruitment of Tsg101 ensure HTLV-1 Gag trafficking towards the multi-vesicular body pathway prior to virus budding. J. Cell Sci. 117, 2357–2367.

Boerkoel, C.F., Takashima, H., Stankiewicz, P., Garcia, C.A., Leber, S.M., Rhee-Morris,L., Lupski, J.R., 2001. Periaxin mutations cause recessive Dejerine–Sottas neu-ropathy. Am. J. Hum. Genet. 68, 325–333.

Boillee, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G.,Kollias, G., Cleveland, D.W., 2006. Onset and progression in inherited ALSdetermined by motor neurons and microglia. Science 312, 1389–1392.

Bolino, A., Bolis, A., Previtali, S.C., Dina, G., Bussini, S., Dati, G., Amadio, S., Del Carro,U., Mruk, D.D., Feltri, M.L., Cheng, C.Y., Quattrini, A., Wrabetz, L., 2004. Disrup-tion of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding andimpaired spermatogenesis. J. Cell Biol. 167, 711–721.

Bolino, A., Muglia, M., Conforti, F.L., LeGuern, E., Salih, M.A., Georgiou, D.M.,Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A.,Gambardella, A., Bono, F., Quattrone, A., Devoto, M., Monaco, A.P., 2000. Char-cot–Marie–Tooth type 4B is caused by mutations in the gene encoding myo-tubularin-related protein-2. Nat. Genet. 25, 17–19.

Bolis, A., Coviello, S., Bussini, S., Dina, G., Pardini, C., Previtali, S.C., Malaguti, M.,Morana, P., Del Carro, U., Feltri, M.L., Quattrini, A., Wrabetz, L., Bolino, A., 2005.Loss of Mtmr2 phosphatase in Schwann cells but not in motor neurons causesCharcot–Marie–Tooth type 4B1 neuropathy with myelin outfoldings. J. Neu-rosci. 25, 8567–8577.

Bolis, A., Coviello, S., Visigalli, I., Taveggia, C., Bachi, A., Chishti, A.H., Hanada, T.,Quattrini, A., Previtali, S.C., Biffi, A., Bolino, A., 2009. Dlg1, Sec8, and Mtmr2regulate membrane homeostasis in Schwann cell myelination. J. Neurosci. 29,8858–8870.

Bolis, A., Zordan, P., Coviello, S., Bolino, A., 2007. Myotubularin-related (MTMR)phospholipid phosphatase proteins in the peripheral nervous system. Mol.Neurobiol. 35, 308–316.

Bonangelino, C.J., Nau, J.J., Duex, J.E., Brinkman, M., Wurmser, A.E., Gary, J.D., Emr,S.D., Weisman, L.S., 2002. Osmotic stress-induced increase of phosphatidyli-nositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p.J. Cell Biol. 156, 1015–1028.

Bonazzi, M., Spano, S., Turacchio, G., Cericola, C., Valente, C., Colanzi, A., Kweon, H.S.,Hsu, V.W., Polishchuck, E.V., Polishchuck, R.S., Sallese, M., Pulvirenti, T., Corda,D., Luini, A., 2005. CtBP3/BARS drives membrane fission in dynamin-indepen-dent transport pathways. Nat. Cell Biol. 7, 570–580.

Bonifacino, J.S., Lippincott-Schwartz, J., 2003. Coat proteins: shaping membranetransport. Nat. Rev. Mol. Cell Biol. 4, 409–414.

Bonne, G., Di Barletta, M.R., Varnous, S., Becane, H.M., Hammouda, E.H., Merlini, L.,Muntoni, F., Greenberg, C.R., Gary, F., Urtizberea, J.A., Duboc, D., Fardeau, M.,Toniolo, D., Schwartz, K., 1999. Mutations in the gene encoding lamin A/C causeautosomal dominant Emery–Dreifuss muscular dystrophy. Nat. Genet. 21, 285–288.

Bonneick, S., Boentert, M., Berger, P., Atanasoski, S., Mantei, N., Wessigk, C., Toyka,K.V., Young, P., Suter, U., 2005. An animal model for Charcot–Marie–Toothdisease type 4B1. Hum. Mol. Genet. 14, 3685–3695.

Bossy-Wetzel, E., Barsoum, M.J., Godzik, A., Schwarzenbacher, R., Lipton, S.A., 2003.Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr. Opin.Cell Biol. 15, 706–716.

Botelho, R.J., Efe, J.A., Teis, D., Emr, S.D., 2008. Assembly of a Fab1 phosphoinositidekinase signaling complex requires the Fig4 phosphoinositide phosphatase. Mol.Cell. Biol. 19, 4273–4286.

Bremner, K.H., Scherer, J., Yi, J., Vershinin, M., Gross, S.P., Vallee, R.B., 2009.Adenovirus transport via direct interaction of cytoplasmic dynein with theviral capsid hexon subunit. Cell Host Microbe 6, 523–535.

Brown, F.C., Pfeffer, S.R., 2010. An update on transport vesicle tethering. Mol.Membr. Biol. 27, 457–461.

Brownlees, J., Ackerley, S., Grierson, A.J., Jacobsen, N.J., Shea, K., Anderton, B.H.,Leigh, P.N., Shaw, C.E., Miller, C.C., 2002. Charcot–Marie–Tooth disease neuro-filament mutations disrupt neurofilament assembly and axonal transport.Hum. Mol. Genet. 11, 2837–2844.

Bucci, C., Chiariello, M., 2006. Signal transduction gRABs attention. Cell. Signal. 18,1–8.

Bucci, C., Chiariello, M., Lattero, D., Maiorano, M., Bruni, C.B., 1999. Interactioncloning and characterization of the cDNA encoding the human prenylated rabacceptor (PRA1). Biochem. Biophys. Res. Commun. 258, 657–662.

Bucci, C., Frunzio, R., Chiariotti, L., Brown, A.L., Rechler, M.M., Bruni, C.B., 1988. Anew member of the ras gene superfamily identified in a rat liver cell line.Nucleic Acids Res. 16, 9979–9993.


Bucci, C., Thomsen, P., Nicoziani, P., McCarthy, J., van Deurs, B., 2000. Rab7: a key tolysosome biogenesis. Mol. Biol. Cell 11, 467–480.

Bui, M., Gilady, S.Y., Fitzsimmons, R.E., Benson, M.D., Lynes, E.M., Gesson, K., Alto,N.M., Strack, S., Scott, J.D., Simmen, T., 2010. Rab32 modulates apoptosis onsetand mitochondria-associated membrane (MAM) properties. J. Biol. Chem. 285.

Cabezas, A., Pattni, K., Stenmark, H., 2006. Cloning and subcellular localization of ahuman phosphatidylinositol 3-phosphate 5-kinase, PIKfyve/Fab1. Gene 371,34–41.

Cai, H., Reinisch, K., Ferro-Novick, S., 2007a. Coats, tethers, Rabs, and SNAREs worktogether to mediate the intracellular destination of a transport vesicle. Dev. Cell12, 671–682.

Cai, H., Yu, S., Menon, S., Cai, Y., Lazarova, D., Fu, C., Reinisch, K., Hay, J.C., Ferro-Novick, S., 2007b. TRAPPI tethers COPII vesicles by binding the coat subunitSec23. Nature 445, 941–944.

Cai, Q., Gerwin, C., Sheng, Z.H., 2005. Syntabulin-mediated anterograde transport ofmitochondria along neuronal processes. J. Cell Biol. 170, 959–969.

Cantalupo, G., Alifano, P., Roberti, V., Bruni, C.B., Bucci, C., 2001. Rab-interactinglysosomal protein (RILP): the Rab7 effector required for transport to lysosomes.EMBO J. 20, 683–693.

Cao, C., Backer, J.M., Laporte, J., Bedrick, E.J., Wandinger-Ness, A., 2008. Sequentialactions of myotubularin lipid phosphatases regulate endosomal PI(3)P andgrowth factor receptor trafficking. Mol. Biol. Cell 19, 3334–3346.

Cao, H., Chen, J., Awoniyi, M., Henley, J.R., McNiven, M.A., 2007. Dynamin 2 mediatesfluid-phase micropinocytosis in epithelial cells. J. Cell Sci. 120, 4167–4177.

Cao, H., Weller, S., Orth, J.D., Chen, J., Huang, B., Chen, J.L., Stamnes, M., McNiven,M.A., 2005. Actin and Arf1-dependent recruitment of a cortactin–dynamincomplex to the Golgi regulates post-Golgi transport. Nat. Cell Biol. 7, 483–492.

Carra, S., Seguin, S.J., Lambert, H., Landry, J., 2008a. HspB8 chaperone activity towardpoly(Q)-containing proteins depends on its association with Bag3, a stimulatorof macroautophagy. J. Biol. Chem. 283, 1437–1444.

Carra, S., Seguin, S.J., Landry, J., 2008b. HspB8 and Bag3: a new chaperone complextargeting misfolded proteins to macroautophagy. Autophagy 4, 237–239.

Carra, S., Sivilotti, M., Chavez Zobel, A.T., Lambert, H., Landry, J., 2005. HspB8, a smallheat shock protein mutated in human neuromuscular disorders, has in vivochaperone activity in cultured cells. Hum. Mol. Genet. 14, 1659–1669.

Cartoni, R., Martinou, J.C., 2009. Role of mitofusin 2 mutations in the physiopathol-ogy of Charcot–Marie–Tooth disease type 2A. Exp. Neurol. 218, 268–273.

Cassereau, J., Chevrollier, A., Gueguen, N., Desquiret, V., Verny, C., Nicolas, G., Dubas,F., Amati-Bonneau, P., Reynier, P., Bonneau, D., Procaccio, V., 2011. Mitochon-drial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involv-ing GDAP1 mutations. Exp. Neurol. 227, 31–41.

Caviston, J.P., Holzbaur, E.L.F., 2009. Huntingtin as an essential integrator ofintracellular vesicular trafficking. Trends Cell Biol. 19, 147–155.

Chang, L., Barlan, K., Chou, Y.H., Grin, B., Lakonishok, M., Serpinskaya, A.S., Shu-maker, D.K., Herrmann, H., Gelfand, V.I., Goldman, R.D., 2009. The dynamicproperties of intermediate filaments during organelle transport. J. Cell Sci. 122,2914–2923.

Chang, L., Kamata, H., Solinas, G., Luo, J.L., Maeda, S., Venuprasad, K., Liu, Y.C., 2006.The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced celldeath by inducing c-FLIP(L) turnover. Cell 124, 601–613.

Chen, H., Chan, D.C., 2009. Mitochondrial dynamics—fusion, fission, movement,and mitophagy—in neurodegenerative diseases. Hum. Mol. Genet. 18, R169–R176.

Chen, H., Detmer, S.A., Ewald, A.J., Griffin, E.E., Fraser, S.E., Chan, D.C., 2003.Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion andare essential for embryonic development. J. Cell Biol. 160, 189–200.

Chen, H., McCaffery, J.M., Chan, D.C., 2007. Mitochondrial fusion protects againstneurodegeneration in the cerebellum. Cell 130, 548–562.

Chen, J.L., Fucini, R.V., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Stamnes, M.,2005. Coatomer-bound Cdc42 regulates dynein recruitment to COPI vesicles. J.Cell Biol. 169, 383–389.

Chen, J.L., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Stamnes, M., 2004a.Cytosol-derived proteins are sufficient for Arp2/3 recruitment and ARF/coat-omer-dependent actin polymerization on Golgi membranes. FEBS Lett. 566,281–286.

Chen, Z.Y., Patel, P.D., Sant, G., Meng, C.X., Teng, K.K., Hempstead, B.L., Lee, F.S.,2004b. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters theintracellular trafficking and activity-dependent secretion of wild-type BDNF inneurosecretory cells and cortical neurons. J. Neurosci. 24, 4401–4411.

Chiariello, M., De Gregorio, L., Vitelli, R., Alifano, P., Dragani, T.A., Bruni, C.B., Bucci,C., 1998. Genetic mapping of the mouse Rab7 gene and pseudogene and of thehuman RAB7 homolog. Mamm. Genome 9, 448–452.

Chierzi, S., Ratto, G.M., Verma, P., Fawcett, J.W., 2005. The ability of axons toregenerate their growth cones depends on axonal type and age, and is regulatedby calcium, cAMP and ERK. Eur. J. Neurosci. 21, 2051–2062.

Chow, C.Y., Zhang, Y., Dowling, J.J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy,M.E., Li, J., Zhang, X., Lupski, J.R., Weisman, L.S., Meisler, M.H., 2007. Mutation ofFIG4 causes neurodegeneration in the pale tremor mouse and patients withCMT4J. Nature 448, 68–72.

Chowdary, T.K., Raman, B., Ramakrishna, T., Rao, C.H., 2004. Mammalian Hsp22 is aheat-inducible small heat-shock protein with chaperone-like activity. Biochem.J. 381, 379–387.

Chowdary, T.K., Raman, B., Ramakrishna, T., Rao, C.H., 2007. Interaction of mam-malian Hsp22 with lipid membranes. Biochem. J. 401, 437–445.

Christoforidis, S., McBride, H.M., Burgoyne, R.D., Zerial, M., 1999. The Rab5 effectorEEA1 is a core component of endosome docking. Nature 397, 621–625.




G Model


Cogli, L., Piro, F., Bucci, C., 2009. Rab7 and the CMT2B disease. Biochem. Soc. Trans.37, 1027–1031.

Cogli, L., Progida, C., Lecci, R., Bramato, R., Kruttgen, A., Bucci, C., 2010. CMT2B-associated Rab7 mutants inhibit neurite outgrowth. Acta Neuropathol. 120,491–501.

Corfas, G., Velardez, M.O., Ko, C.P., Ratner, N., Peles, E., 2004. Mechanisms and rolesof axon-Schwann cell interactions. J. Neurosci. 24, 9250–9260.

Court, F.A., Brophy, P.J., Ribchester, R.R., 2008. Remodeling of motor nerve terminalsin demyelinating axons of periaxin-null mice. Glia 56, 471–479.

Cuervo, A., Dice, J., 1996. A receptor for the selective uptake and degradation ofproteins by lysosomes. Science 273, 501–503.

Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., Sulzer, D., 2004. Impaireddegradation of mutant a-Synuclein by Chaperone-mediated autophagy. Sci-ence 305, 1292–1295.

Cuesta, A., Pedrola, L., Sevilla, T., Garcıa-Planells, J., Chumillas, M.J., Mayordomo, F.,LeGuern, E., Marın, I., Vılchez, J.J., Palau, F., 2002. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease. Nat. Genet. 30, 22–25.

Cui, Q., 2006. Actions of neurotrophic factors and their signaling pathways inneuronal survival and axonal regeneration. Mol. Neurobiol. 33, 155–179.

Custer, S.K., Garden, G.A., Gill, N., Rueb, U., Libby, R.T., Schultz, C., Guyenet, S.J.,Deller, T., Westrum, L.E., Sopher, B.L., La Spada, A.R., 2006. Bergmann gliaexpression of polyglutamine-expanded ataxin-7 produces neurodegenerationby impairing glutamate transport. Nat. Neurosci. 9, 1302–1311.

D’Adamo, P., Menegon, A., Lo Nigro, C., Grasso, M., Gulisano, M., Tamanini, F.,Bienvenu, T., Gedeon, A., Oostra, B., Wu, S., Tandon, A., Valtorta, F., Balch, W.,Chelly, J., Toniolo, D., 1998. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat. Genet. 19, 134–139.

Dalfo, E., Gomez-Isla, T., Rosa, J., Nieto Bodelon, M., CuadradoTejedor, M., Barra-china, M., Ambrosio, S., Ferrer, I., 2004. Abnormal alpha-synuclein interactionswith Rab proteins in alpha-synuclein A30P transgenic mice. J. Neuropathol. Exp.Neurol. 63, 302–313.

Damke, H., Baba, T., Warnock, D.E., Schmid, S.L., 1994. Induction of mutant dynaminspecifically blocks endocytic coated vesicle formation. J. Cell Biol. 127, 915–934.

D’Azzo, A., Bongiovanni, A., Nastasi, T., 2005. E3 ubiquitin ligases as regulators ofmembrane protein trafficking and degradation. Traffic 6, 429–441.

de Brito, O.M., Scorrano, L., 2008a. Mitofusin 2 tethers endoplasmic reticulum tomitochondria. Nature 456, 605–610.

de Brito, O.M., Scorrano, L., 2008b. Mitofusin 2: a mitochondria-shaping proteinwith signaling roles beyond fusion. Antioxid. Redox Signal. 10, 621–633.

de Brito, O.M., Scorrano, L., 2010. An intimate liaison: spatial organization of theendoplasmic reticulum-mitochondria relationship. EMBO J. 29, 2715–2723.

de Brouwer, A.P., van Bokhoven, H., Nabuurs, S.B., Arts, W.F., Christodoulou, J.,Duley, J., 2010. PRPS1 mutations: four distinct syndromes and potential treat-ment. Am. J. Hum. Genet. 86, 506–518.

De Camilli, P., Emr, S.D., McPherson, P.S., Novick, P., 1996. Phosphoinositides asregulators in membrane traffic. Science 271, 1533–1539.

De Jonghe, P., Mersivanova, I., Nelis, E., Del Favero, J., Martin, J.-J., Van Broeckhoven,C., Evgrafov, O., Timmerman, V., 2001. Further evidence that neurofilament lightchain gene mutations can cause Charcot–Marie–Tooth disease type 2E. Ann.Neurol. 49, 245–249.

De Lartigue, J., Polson, H., Feldman, M., Shokat, K., Tooze, S.A., Urbe, S., Clague, M.J.,2009. PIKfyve regulation of endosome-linked pathways. Traffic 10, 883–893.

de Leeuw, C.N., 2008. CMT4J: Charcot–Marie–Tooth disorder caused by mutationsin FIG4. Clin. Genet. 73, 318–319.

De Luca, A., Progida, C., Spinosa, M.R., Alifano, P., Bucci, C., 2008. Characterization ofthe Rab7K157N mutant protein associated with Charcot–Marie–Tooth type 2B.Biochem. Biophys. Res. Commun. 372, 283–287.

De Sandre-Giovannoli, A., Chaouch, M., Kozlov, S., Vallat, J.M., Tazir, M., Kassouri, N.,Szepetowski, P., Hammadouche, T., Vandenberghe, A., Stewart, C.L., Grid, D.,Levy, N., 2002. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human(Charcot–Marie–Tooth disorder type 2) and mouse. Am. J. Hum. Genet. 70, 726–736.

De Vos, K.J., Chapman, A.L., Tennant, M.E., Manser, C., Tudor, E.L., Lau, K.F., Brown-lees, J., Ackerley, S., Shaw, P.J., McLoughlin, D.M., Shaw, C.E., Leigh, P.N., Miller,C.C., Grierson, A.J., 2007. Familial amyotrophic lateral sclerosis-linked SOD1mutants perturb fast axonal transport to reduce axonal mitochondria content.Hum. Mol. Genet. 16, 2720–2728.

De Vos, K.J., Grierson, A.J., Ackerley, S., Miller, C.C., 2008. Role of axonal transport inneurodegenerative diseases. Annu. Rev. Neurosci. 31, 151–173.

de Waegh, S., Brady, S.T., 1990. Altered slow axonal transport and regeneration in amyelin-deficient mutant mouse: the trembler as an in vivo model for Schwanncell-axon interactions. J. Neurosci. 10, 1855–1865.

de Waegh, S.M., Lee, V.M., Brady, S.T., 1992. Local modulation of neurofilamentphosphorylation, axonal caliber, and slow axonal transport by myelinatingSchwann cells. Cell 68, 451–463.

Deinhardt, K., Salinas, S., Verastegui, C., Watson, R., Worth, D., Hanrahan, S., Bucci, C.,Schiavo, G., 2006. Rab5 and Rab7 control endocytic sorting along the axonalretrograde transport pathway. Neuron 52, 293–305.

del Toro, D., Alberch, J., Lazaro-Dieguez, F., Martın-Ibanez, R., Xifro, X., Egea, G.,Canals, J.M., 2009. Mutant huntingtin impairs post-Golgi trafficking to lyso-somes by delocalizing optineurin/Rab8 complex from the Golgi apparatus. Mol.Biol. Cell 20, 1478–1492.

Delague, V., Jacquier, A., Hamadouche, T., Poitelon, Y., Baudot, C., Boccaccio, I.,Chouery, E., Chaouch, M., Kassouri, N., Jabbour, R., Grid, D., Megarbane, A.,


Haase, G., Levy, N., 2007. Mutations in FGD4 encoding the Rho GDP/GTPexchange factor FRABIN cause autosomal recessive Charcot–Marie–Tooth type4H. Am. J. Hum. Genet. 81, 1–16.

Delcroix, J.-D., Valletta, J.S., Wu, C., Hunt, S.J., Kowal, A.S., Mobley, W.C., 2003. NGFsignaling in sensory neurons: evidence that early endosomes carry NGF retro-grade signals. Neuron 39, 69–84.

Deng, H.X., Klein, C.J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.J., Yang, Y., Zhai, H.,Siddique, N., Hedley-Whyte, E.T., Delong, R., Martina, M., Dyck, P.J., Siddique, T.,2010. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorderscaused by alterations in TRPV4. Nat. Genet. 42, 165–169.

DePina, A.S., Langford, G.M., 1999. Vesicle transport: the role of actin filaments andmyosin motors. Microsc. Res. Tech. 47, 93–106.

Detmer, S.A., Vande Velde, C., Cleveland, D.W., Chan, D.C., 2008. Hindlimb gaitdefects due to motor axon loss and reduced distal muscles in a transgenicmouse model of Charcot–Marie–Tooth type 2A. Hum. Mol. Genet. 17, 367–375.

Di Giorgio, F.P., Carrasco, M.A., Siao, M.C., Maniatis, T., Eggan, K., 2007. Non-cellautonomous effect of glia on motor neurons in an embryonic stem cell-basedALS model. Nat. Neurosci. 10, 608–614.

Di Paolo, G., De Camilli, P., 2006. Phosphoinositides in cell regulation and membranedynamics. Nature 443, 651–657.

Diatloff-Zito, C., Gordon, A.J., Duchaud, E., Merlin, G., 1995. Isolation of an ubiqui-tously expressed cDNA encoding human dynamin II, a member of the large GTP-binding protein family. Gene 163, 301–306.

Dierick, I., Irobi, J., De Jonghe, P., Timmerman, V., 2005. Small heat shock proteins ininherited peripheral neuropathies. Ann. Med. 37, 413–422.

DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., Martin, E.,Vonsattel, J.-P., Carraway, R., Reeves, S.A., Boyce, F.M., Aronin, N., 1995. Hun-tingtin is a cytoplasmic protein associated with vesicles in human and rat brainneurons. Neuron 14, 1075–1081.

Dong, J., Misselwitz, R., Welfle, H., Westermann, P., 2000. Expression and purifica-tion of dynamin II domains and initial studies on structure and function. ProteinExpr. Purif. 20, 314–323.

Doshi, B.M., Hightower, L.E., Lee, J., 2009. The role of Hsp27 and actin in theregulation of movement in human cancer cells responding to heat shock. CellStress Chaperones 14, 445–457.

Dove, S.K., Cooke, F.T., Douglas, M.R., Sayers, L.G., Parker, P.J., Michell, R.H., 1997.Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis. Na-ture 390.

Dove, S.K., McEwen, R.K., Mayes, A., Hughes, D.C., Beggs, J.D., Michell, R.H., 2002.Vac14 controls PtdIns(3,5)P2 synthesis and Fab1-dependent protein traffickingto the multivesicular body. Curr. Biol. 12, 885–893.

Dove, S.K., Piper, R.C., McEwen, R.K., Yu, J.W., King, M.C., Hughes, D.C., Thuring, J.,Holmes, A.B., Cooke, F.T., Michell, R.H., Parker, P.J., Lemmon, M.A., 2004. Svp1pdefines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J. 23,1922–1933.

Dubois, M.F., Hovanessian, A.G., Bensaude, O., 1991. Heat shock-induced denatur-ation of proteins. Characterization of the insolubilization of the interferon-induced p68 kinase. J. Biol. Chem. 266, 9707–9711.

Dubourg, O., Azzedine, H., Verny, C., Durosier, G., Birouk, N., Gouider, R., Salih, M.,Bouhouche, A., Thiam, A., Grid, D., Mayer, M., Ruberg, M., Tazir, M., Brice, A.,LeGuern, E., 2006. Autosomal-recessive forms of demyelinating Charcot–Marie–Tooth disease. Neuromol. Med. 8, 75–86.

Duex, J.E., Tang, F., Weisman, L.S., 2006. The Vac14p-Fig4p complex acts indepen-dently of Vac7p and couples PI3,5P2 synthesis and turnover. J. Cell Biol. 172,693–704.

Durieux, A.C., Prudhon, B., Guicheney, P., Bitoun, M., 2010. Dynamin 2 and humandiseases. J. Mol. Med. 88, 339–350.

Dyck, P.J., Lambert, E.H., 1968. Lower motor and primary sensory neuron diseaseswith peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologicfindings in hereditary polyneuropathies. Arch. Neurol. 18, 603–618.

Eaton, H.E., Desrochers, G., Drory, S.B., Metcalf, J., Angers, A., Brunetti, C.R., 2011.SIMPLE/LITAF expression induces the translocation of the ubiquitin ligase itchtowards the lysosomal compartments. PLoS ONE 6, e16873.

Edinger, A.L., Cinalli, R.M., Thompson, C.B., 2003. Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter ex-pression. Dev. Cell 5, 571–582.

Edvardson, S., Shaag, A., Kolesnikova, O., Gomori, J.M., Tarassov, I., Einbinder, T.,Saada, A., Elpeleg, O., 2007. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia.Am. J. Hum. Genet. 81, 857–862.

Efe, J.A., Botelho, R.J., Emr, S.D., 2005. The Fab1 phosphatidylinositol kinase pathwayin the regulation of vacuole morphology. Curr. Opin. Cell Biol. 17, 402–408.

Efe, J.A., Botelho, R.J., Emr, S.D., 2007. Atg18 regulates organelle morphology andFab1 kinase activity independent of its membrane recruitment by phosphati-dylinositol 3,5-bisphosphate. Mol. Biol. Cell 18, 4232–4244.

Efendiev, R., Yudowski, G.A., Zwiller, J., Leibiger, B., Katz, A.I., Berggren, P.O.,Pedemonte, C.H., Leibiger, I.B., Bertorello, A.M., 2002. Relevance of dopaminesignals anchoring dynamin-2 to the plasma membrane during Na+, K+-ATPaseendocytosis. J. Biol. Chem. 277, 44108–44114.

Ehlers, M.D., Kaplan, D.R., Price, D.L., Koliatsos, V.E., 1995. NGF-stimulated retro-grade transport of trkA in the mammalian nervous system. J. Cell Biol. 130, 149–156.

Eriksson, J.E., Dechat, T., Grin, B., Helfand, B., Mendez, M., Pallari, H.M., Goldman, R.,2009. Introducing intermediate filaments: from discovery to disease. J. Clin.Invest. 119, 1763–1771.




G Model


Evgrafov, O.V., Mersiyanova, I.V., Irobi, J., Van den Bosch, L., Dierick, I., Schagina, O.,2004. Mutant small heat shock protein 27 causes axonal Charcot–Marie–Toothdisease and distal hereditary motor neuropathy. Nat. Genet. 36, 602–606.

Ezratty, E.J., Partridge, M.A., Gundersen, G.G., 2005. Microtubule-induced focaladhesion disassembly is mediated by dynamin and focal adhesion kinase.Nat. Cell Biol. 7, 581–590.

Fabrizi, G.M., Cavallaro, T., Angiari, C., Bertolasi, L., Cabrini, I., Ferrarini, M., Rizzuto,N., 2004. Giant axon and neurofilament accumulation in Charcot–Marie–Toothdisease type 2E. Neurology 62, 1429–1431.

Fabrizi, G.M., Cavallaro, T., Angiari, C., Cabrini, I., Taioli, F., Malerba, G., Bertolasi, L.,Rizzuto, N., 2007a. Charcot–Marie–Tooth disease type 2E, a disorder of thecytoskeleton. Brain 130, 394–403.

Fabrizi, G.M., Ferrarini, M., Cavallaro, T., Cabrini, I., Cerini, R., Bertolasi, L., Rizzuto, N.,2007b. Two novel mutations in dynamin-2 cause axonal Charcot–Marie-Toothdisease. Neurology 69, 291–295.

Fairweather, N., Bell, C., Cochrane, S., Chelly, J., Wang, S., Mostacciuolo, M.L.,Monaco, A.P., Haites, N.E., 1994. Mutations in the connexin 32 gene in X-linkeddominant Charcot–Marie–Tooth disease (CMTX1). Hum. Mol. Genet. 3, 29–34.

Fatkin, D., MacRae, C., Sasaki, T., Wolff, M.R., Porcu, M., Frenneaux, M., Atherton, J.,Vidaillet, H.J.J., Spudich, S., De Girolami, U., Seidman, J.G., Seidman, C., Muntoni,F., Muehle, G., Johnson, W., McDonough, B., 1999. Missense mutations in the roddomain of the lamin A/C gene as causes of dilated cardiomyopathy andconduction-system disease. N. Engl. J. Med. 341, 1715–1724.

Fei, W., Li, H., Shui, G., Kapterian, T.S., Bielby, C., Du, X., Brown, A.J., Li, P., Wenk, M.R.,Liu, P., Yang, H., 2011. Molecular characterization of seipin and its mutants:implications for seipin in triacylglycerol synthesis. J. Lipid Res. 52, 2136–2147.

Ferguson, C.J., Lenk, G.M., Meisler, M.H., 2009. Defective autophagy in neurons andastrocytes from mice deficient in PI(3,5)P2. Hum. Mol. Genet. 18, 4968–4978.

Ferguson, C.J., Lenk, G.M., Meisler, M.H., 2010. PtdIns(3,5)P2 and autophagy inmouse models of neurodegeneration. Autophagy 6, 170–171.

Fish, K.N., Schmid, S.L., Damke, H., 2000. Evidence that dynamin-2 functions as asignal-transducing GTPase. J. Cell Biol. 150, 145–154.

Foletti, D.L., Prekeris, R., Scheller, R.H., 1999. Generation and maintenance ofneuronal polarity. Neuron 23, 641–644.

Fontaine, J.M., Sun, X., Benndorf, R., Welsh, M.J., 2005. Interaction of HSP22 (HspB8)with HSP20, aB-crystallin, and HspB3. Biochem. Biophys. Res. Commun. 337,1006–1011.

Fortun, J., Go, J.C., Li, J., Amici, S.A., Dunn, W.A.J., Notterpek, L., 2006. Alterations indegradative pathways and protein aggregation in a neuropathy model based onPMP22 overexpression. Neurobiol. Dis. 22, 153–164.

Foth, B.J., Goedecke, M.C., Soldati, D., 2006. New insights into myosin evolution andclassification. Proc. Natl. Acad. Sci. U.S.A. 103, 3681–3686.

Franklin, N.E., Taylor, G.S., Vacratsis, P.O., 2011. Endosomal targeting of the phos-phoinositide 3-phosphatase MTMR2 is regulated by an N-terminal phosphor-ylation site. J. Biol. Chem. 286, 15841–15853.

Fransson, S., Ruusala, A., Aspenstrom, P., 2006. The atypical Rho GTPases Miro-1 andMiro-2 have essential roles in mitochondrial trafficking. Biochem. Biophys. Res.Commun. 344, 500–510.

Frederick, R.L., Shaw, J.M., 2007. Moving mitochondria: establishing distribution ofan essential organelle. Traffic 8, 1668–1675.

Fuchs, E., 1994. Intermediate filaments and disease: mutations that cripple cellstrength. J. Cell Biol. 125, 511–516.

Fuchs, E., Weber, K., 1994. Intermediate filaments: structure, dynamics, function,and disease. Annu. Rev. Biochem. 63, 345–382.

Fujita, A., Kurachi, Y., 2000. SAP family proteins. Biochem. Biophys. Res. Commun.269, 1–6.

Fujita, Y., Krause, G., Scheffner, M., Zechner, D., Leddy, H.E., Behrens, J., Sommer, T.,Birchmeier, W., 2002. Hakai, a c-Cbl-like protein, ubiquitinates and inducesendocytosis of the E-cadherin complex. Nat. Cell Biol. 4, 222–231.

Gallardo, E., Claeys, K.G., Nelis, E., Garcia, A., Canga, A., Combarros, O., Timmerman,V., De Jonghe, P., Berciano, J., 2008. Magnetic resonance imaging findings of legmusculature in Charcot–Marie-Tooth disease type 2 due to dynamin 2 muta-tion. J. Neurol. 255, 986–992.

Garcıa-Arencibia, M., Hochfeld, W.E., Toh, P.P., Rubinsztein, D.C., 2010. Autophagy, aguardian against neurodegeneration. Semin. Cell Dev. Biol. 21, 691–698.

Garcia-Reitbock, P., Anichtchik, O., Bellucci, A., Iovino, M., Ballini, C., Fineberg, E.,Ghetti, B., Della Corte, L., Spano, P., Tofaris, G.K., Goedert, M., Spillantini, M.G.,2010. SNARE protein redistribution and synaptic failure in a transgenic mousemodel of Parkinson’s disease. Brain 133, 2032–2044.

Garrus, J.E., von Schwedler, U.K., Pornillos, O.W., Morham, S.G., Zavitz, K.H., Wang,H.E., Wettstein, D.A., Stray, K.M., Cote, M., Rich, R.L., Myszka, D.G., Sundquist,W.I., 2001. Tsg101 and the vacuolar protein sorting pathway are essential forHIV-1 budding. Cell 107, 55–65.

Gary, J.D., Sato, T.K., Stefan, C.J., Bonangelino, C.J., Weisman, L.S., Emr, S.D., 2002.Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway byVac7 protein and Fig4, a polyphosphoinositide phosphatase family member.Mol. Biol. Cell 13, 1238–1251.

Gary, J.D., Wurmser, A.E., Bonangelino, C.J., Weisman, L.S., Emr, S.D., 1998. Fab1p isessential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar sizeand membrane homeostasis. J. Cell Biol. 143, 65–79.

Geppert, M., Goda, Y., Stevens, C.F., Sudhof, T.C., 1997. The small GTP-bindingprotein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387,810–814.

Gerding, W.M., Koetting, J., Epplen, J.T., Neusch, C., 2009. Hereditary motor andsensory neuropathy caused by a novel mutation in LITAF. Neuromuscul. Disord.19, 701–703.


Gill, S.R., Schroer, T.A., Szilak, I., Steuer, E.R., Sheetz, M.P., Cleveland, D.W., 1991.Dynactin, a conserved, ubiquitously expressed component of an activator ofvesicle motility mediated by cytoplasmic dynein. J. Cell Biol. 115, 1639–1650.

Gillespie, C.S., Sherman, D.L., Blair, G.E., Brophy, P.J., 1994. Periaxin, a novel proteinof myelinating Schwann cells with a possible role in axonal ensheathment.Neuron 12, 497–508.

Gillooly, D.J., Morrow, I.C., Lindsay, M., Gould, R., Bryant, N.J., Gaullier, J.M., Parton,R.G., Stenmark, H., 2000. Localization of phosphatidylinositol 3-phosphate inyeast and mammalian cells. EMBO J. 19, 4577–4588.

Gissen, P., Johnson, C.A., Morgan, N.V., Stapelbroek, J.M., Forshew, T., Cooper, W.N.,McKiernan, P.J., Klomp, L.W., Morris, A.A., Wraith, J.E., McClean, P., Lynch, S.A.,Thompson, R.J., Lo, B., Quarrell, O.W., Di Rocco, M., Trembath, R.C., Mandel, H.,Wali, S., Karet, F.E., Knisely, A.S., Houwen, R.H., Kelly, D.A., Maher, E.R., 2004.Mutations in VPS33B, encoding a regulator of SNARE-dependent membranefusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.Nat. Genet. 36, 400–404.

Gitler, A., Bevis, B., Shorter, J., Strathearn, K., Hamamichi, S., Su, L., Caldwell, K.,Caldwell, G., Rochet, J., McCaffery, J., Barlowe, C., Lindquist, S., 2008. TheParkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis.Proc. Natl. Acad. Sci. U.S.A. 105, 145–150.

Gitler, D., Spira, M.E., 1998. Real time imaging of calcium-induced localized pro-teolytic activity after axotomy and its relation to growth cone formation.Neuron 20, 1123–1135.

Glater, E.E., Megeath, L.J., Stowers, R.S., Schwarz, T.L., 2006. Axonal transport ofmitochondria requires milton to recruit kinesin heavy chain and is light chainindependent. J. Cell Biol. 173, 545–557.

Gober, M.D., Smith, C.C., Ueda, K., Toretsky, J.A., Aurelian, L., 2003. Forced expressionof the H11 heat shock protein can be regulated by DNA methylation and triggerapoptosis in human cells. J. Biol. Chem. 278, 37600–37609.

Gold, E.S., Underhill, D.M., Morrissette, N.S., Guo, J., McNiven, M.A., Aderem, A.,1999. Dynamin 2 is required for phagocytosis in macrophages. J. Exp. Med. 190,1849–1856.

Goldstein, L.S., Yang, Z., 2000. Microtubule-based transport systems in neurons: theroles of kinesins and dyneins. Annu. Rev. Neurosci. 23, 39–71.

Goryunov, D., Nightingale, A., Bornfleth, L., Leung, C., Liem, R.K., 2008. Multipledisease-linked myotubularin mutations cause NFL assembly defects in culturedcells and disrupt myotubularin dimerization. J. Neurochem. 104, 1536–1552.

Gougeon, P.Y., Prosser, D.C., Da-Silva, L.F., Ngsee, J.K., 2002. Disruption of Golgimorphology and trafficking in cells expressing mutant prenylated rab acceptor-1. J. Biol. Chem. 277, 36408–36414.

Grimes, M.L., Beattie, E., Mobley, W.C., 1997. A signaling organelle containing thenerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl. Acad.Sci. U.S.A. 94, 9909–9914.

Grimes, M.L., Zhou, J., Beattie, E.C., Yuen, E.C., Hall, D.E., Valletta, J.S., Topp, K.S.,LaVail, J.H., Bunnett, N.W., Mobley, W.C., 1996. Endocytosis of activated TrkA:evidence that Nerve Growth Factor induces formation of signaling endosomes. J.Neurosci. 16, 7950–7964.

Grosshans, B.L., Ortiz, D., Novick, P., 2006. Rabs and their effectors: achievingspecificity in membrane traffic. Proc. Natl. Acad. Sci. U.S.A. 103, 11821–11827.

Guan, K., Farh, L., Marshall, T.K., Deschenes, R.J., 1993. Normal mitochondrialstructure and genome maintenance in yeast requires the dynamin-like productof the MGM1 gene. Curr. Genet. 24, 141–148.

Guan, R.J., Ford, H.L., Fu, Y., Li, Y., Shaw, L.M., Pardee, A.B., 2000. Drg-1 as adifferentiation-related, putative metastatic suppressor gene in human coloncancer. Cancer Res. 60, 749–755.

Guay, J., Lambert, H., Gingras-Breton, G., Lavoie, J.N., Huot, J., Landry, J., 1997.Regulation of actin filament dynamics by p38 map kinase-mediated phosphor-ylation of heat shock protein 27. J. Cell Sci. 110, 357–368.

Guernsey, D.L., Jiang, H., Bedard, K., Evans, S.C., Ferguson, M., Matsuoka, M.,Macgillivray, C., Nightingale, M., Perry, S., Rideout, A.L., Orr, A., Ludman, M.,Skidmore, D.L., Benstead, T., Samuels, M.E., 2010. Mutation in the gene encodingubiquitin ligase LRSAM1 in patients with Charcot–Marie–Tooth disease. PLoSGenet. 6, e1001081.

Guilbot, A., Williams, A., Ravise, N., Verny, C., Brice, A., Sherman, D.L., Brophy, P.J.,LeGuern, E., Delague, V., Bareil, C., Megarbane, A., Claustres, M., 2001. A muta-tion in periaxin is responsible for CMT4F, an autosomal recessive form ofCharcot–Marie–Tooth disease. Hum. Mol. Genet. 10, 415–421.

Gumy, L.F., Tan, C.L., Fawcett, J.W., 2010. The role of local protein synthesis anddegradation in axon regeneration. Exp. Neurol. 223, 28–37.

Gunawardena, S., Her, L.-S., Brusch, R.G., Laymon, R.A., Niesman, I.R., Gordesky-Gold, B., Sintasath, L., Bonini, N.M., Goldstein, L.S.B., 2003. Disruption of axonaltransport by loss of huntingtin or expression of pathogenic polyQ proteins inDrosophila. Neuron 40, 25–40.

Guo, X., Macleod, G.T., Wellington, A., Hu, F., Panchumarthi, S., Schoenfield, M.,Marin, L., Charlton, M.P., Atwood, H.L., Zinsmaier, K.E., 2005. The GTPase dMirois required for axonal transport of mitochondria to Drosophila synapses.Neuron 47, 379–393.

Guo, Y., Punj, V., Sengupta, D., Linstedt, A.D., 2008. Coat-tether interaction in Golgiorganization. Mol. Biol. Cell 19, 2830–2843.

Gusev, N.B., Bogatcheva, N.V., Marston, S.B., 2002. Structure and properties of smallheat shock proteins (sHsp) and their interaction with cytoskeleton proteins.Biochemistry 67, 511–519.

Guthrie, C.R., Kraemer, B.C., 2011. Proteasome inhibition drives HDAC6-dependentrecruitment of tau to aggresomes. J. Mol. Neurosci. 45, 32–41.

Haglund, K., Di Fiore, P.P., Dikic, I., 2003. Distinct monoubiquitin signals in receptorendocytosis. Trends Biochem. Sci. 28, 598–603.




G Model


Hailey, D.W., Rambold, A.S., Satpute-Krishnan, P., Mitra, K., Sougrat, R., Kim, P.K.,Lippincott-Schwartz, J., 2010. Mitochondria supply membranes for autophago-some biogenesis during starvation. Cell 141, 656–667.

Haller, O., Kochs, G., 2002. Interferon-induced mx proteins: dynamin-like GTPaseswith antiviral activity. Traffic 3, 710–717.

Hamao, K., Morita, M., Hosoya, H., 2009. New function of the proline rich domain indynamin-2 to negatively regulate its interaction with microtubules in mam-malian cells. Exp. Cell Res. 315, 1336–1345.

Hanemann, C.O., Gabreels-Festen, A.A., 2002. Secondary axon atrophy and neuro-logical dysfunction in demyelinating neuropathies. Curr. Opin. Neurol. 15, 611–615.

Hansen, C.G., Nichols, B.J., 2010. Exploring the caves: cavins, caveolins and caveolae.Trends Cell Biol. 20, 177–186.

Hantke, J., Chandler, D., King, R., Wanders, R.J., Angelicheva, D., Tournev, I., McNa-mara, E., Kwa, M., Guergueltcheva, V., Kaneva, R., Baas, F., Kalaydjieva, L., 2009. Amutation in an alternative untranslated exon of hexokinase 1 associated withhereditary motor and sensory neuropathy – Russe (HMSNR). Eur. J. Hum. Genet.17, 1606–1614.

Harding, A.E., Thomas, P.K., 1980. The clinical features of hereditary motor andsensory neuropathy types I and II. Brain 103, 259–280.

Harris, K.P., Tepass, U., 2010. Cdc42 and vesicle trafficking in polarized cells. Traffic11, 1272–1279.

Harrison, R., Bucci, C., Vieira, O., Schroer, T., Grinstein, S., 2003. Phagosomes fusewith late endosomes and/or lysosomes by extension of membrane protru-sions along microtubules: role of Rab7 and RILP. Mol. Cell. Biol. 23, 6494–6506.

Haslbeck, M., Franzmann, T., Weinfurtner, D., Buchner, J., 2005. Some like it hot: thestructure and function of small heat-shock proteins. Nat. Struct. Mol. Biol. 12,842–846.

Hattula, K., Peranen, J., 2000. FIP-2, a coiled-coil protein, links Huntingtin to Rab8and modulates cellular morphogenesis. Curr. Biol. 10, 1603–1606.

He, B., Guo, W., 2009. The exocyst complex in polarized exocytosis. Curr. Opin. CellBiol. 21, 537–542.

Head, M.W., Corbin, E., Goldman, J.E., 1993. Overexpression and abnormal modifi-cation of the stress proteins alpha B-crystallin and HSP27 in Alexander disease.Am. J. Pathol. 143, 1743–1753.

Heasman, S.J., Ridley, A.J., 2008. Mammalian Rho GTPases: new insights into theirfunctions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9, 690–701.

Hehnly, H., Stamnes, M., 2007. Regulating cytoskeleton-based vesicle motility. FEBSLett. 581, 2112–2118.

Henley, J.R., Krueger, E.W., Oswald, B.J., McNiven, M.A., 1998. Dynamin-mediatedinternalization of caveolae. J. Cell Biol. 141, 85–99.

Hickey, C.M., Wickner, W., 2010. HOPS initiates vacuole docking by tetheringmembranes before trans-SNARE complex assembly. Mol. Biol. Cell 21, 2297–2305.

Hilliard, M.A., 2009. Axonal degeneration and regeneration: a mechanistic tug-of-war. J. Neurochem. 108, 23–32.

Hirata, K., He, J., Hirakawa, Y., Liu, W., Wang, S., Kawabuchi, M., 2003. HSP27 ismarkedly induced in Schwann cell columns and associated regenerating axons.Glia 42, 1–11.

Hirokawa, N., 1998. Kinesin and dynein superfamily proteins and the mechanism oforganelle transport. Science 279, 519–526.

Hirokawa, N., Niwa, S., Tanaka, Y., 2010. Molecular motors in neurons: transportmechanisms and roles in brain function, development, and disease. Neuron 68,610–638.

Hirokawa, N., Takemura, R., 2003. Biochemical and molecular characterization ofdiseases linked to motor proteins. Trends Biochem. Sci. 28, 558–565.

Hoffner, G., Kahlem, P., Djian, P., 2002. Perinuclear localization of huntingtin as aconsequence of its binding to microtubules through an interaction with b-tubulin: relevance to Huntington’s disease. J. Cell Sci. 115, 941–948.

Hollenbeck, P.J., Saxton, W.M., 2005. The axonal transport of mitochondria. J. CellSci. 118, 5411–5419.

Holzbaur, E.L., Vallee, R.B., 1994. DYNEINS: molecular structure and cellular func-tion. Annu. Rev. Cell Biol. 10, 339–372.

Horiguchi, K., Hanada, T., Fukui, Y., Chishti, A.H., 2006. Transport of PIP3 by GAKIN, akinesin-3 family protein, regulates neuronal cell polarity. J. Cell Biol. 174, 425–436.

Horiuchi, D., Barkus, R.V., Pilling, A.D., Gassman, A., Saxton, W.M., 2005. APLIP1, akinesin binding JIP-1/JNK scaffold protein, influences the axonal transport ofboth vesicles and mitochondria in Drosophila. Curr. Biol. 15.

Horton, A.C., Ehlers, M.D., 2003. Neuronal polarity and trafficking. Neuron 40, 277–295.

Houlden, H., Blake, J., Reilly, M.M., 2004. Hereditary sensory neuropathies. Curr.Opin. Neurol. 17, 569–577.

Houlden, H., Reilly, M.M., 2006. Molecular genetics of autosomal-dominant demy-elinating Charcot–Marie–Tooth disease. Neuromol. Med. 8, 43–62.

Howe, C.L., Mobley, W.C., 2005. Long-distance retrograde neurotrophic signaling.Curr. Opin. Neurobiol. 15, 40–48.

Huang, J., Klionsky, D.J., 2007. Autophagy and human disease. Cell cycle 6, 1837–1849.

Huebner, E.A., Strittmatter, S.M., 2009. Axon regeneration in the peripheral andcentral nervous systems. Results Probl. Cell Differ. 48, 339–351.

Hunter, M., Angelicheva, D., Tournev, I., Ingley, E., Chan, D.C., Watts, G.F., Kre-mensky, I., Kalaydjieva, L., 2005. NDRG1 interacts with APO A-I and A-II and is afunctional candidate for the HDL-C QTL on 8q24. Biochem. Biophys. Res.Commun. 332, 982–992.


Hunter, M., Bernard, R., Freitas, E., Boyer, A., Morar, B., Martins, I.J., Tournev, I.,Jordanova, A., Guergelcheva, V., Ishpekova, B., Kremensky, I., Nicholson, G.,Schlotter, B., Lochmuller, H., Voit, T., Colomer, J., Thomas, P.K., Levy, N., Kalayd-jieva, L., 2003. Mutation screening of the N-myc downstream-regulated gene 1(NDRG1) in patients with Charcot–Marie–Tooth Disease. Hum. Mutat. 22, 129–135.

Hutagalung, A.H., Novick, P., 2011. Role of Rab GTPases in membrane traffic and cellphysiology. Physiol. Rev. 91, 119–149.

Hutchison, C.J., Worman, H.J., 2004. A-type lamins: guardians of the soma? Nat. CellBiol. 6, 1062–1067.

Ikeda, W., Nakanishi, H., Tanaka, Y., Tachibana, K., Takai, Y., 2001. Cooperation ofCdc42 small G protein-activating and actin filament-binding activities of frabinin microspike formation. Oncogene 20, 3457–3463.

Ikonomov, O.C., Sbrissa, D., Fenner, H., Shisheva, A., 2009. PIKfyve-ArPIKfyve-Sac3core complex: contact sites and their consequence for Sac3 phosphataseactivity and endocytic membrane homeostasis. J. Biol. Chem. 284, 35794–35806.

Ikonomov, O.C., Sbrissa, D., Fligger, J., Delvecchio, K., Shisheva, A., 2010. ArPIKfyveregulates Sac3 protein abundance and turnover: disruption of the mechanismby Sac3I41T mutation causing Charcot–Marie–Tooth 4J disorder. J. Biol. Chem.285, 26760–26764.

Ikonomov, O.C., Sbrissa, D., Mlak, K., Deeb, R., Fligger, J., Soans, A., Finley, R.L.J.,Shisheva, A., 2003. Active PIKfyve associates with and promotes the membraneattachment of the late endosome-to-trans-Golgi network transport factor Rab9effector p40. J. Biol. Chem. 278, 50863–50871.

Ingham, R.J., Gish, G., Pawson, T., 2004. The Nedd4 family of E3 ubiquitin ligases:functional diversity within a common modular architecture. Oncogene 23,1972–1984.

Ionasescu, V., Searby, C., Ionasescu, R., 1994. Point mutations of the connexin32(GJB1) gene in X-linked dominant Charcot–Marie–Tooth neuropathy. Hum.Mol. Genet. 3, 355–358.

Irobi, J., Almeida-Souza, L., Asselbergh, B., De Winter, V., Goethals, S., Dierick, I.,Krishnan, J., Timmermans, J.P., Robberecht, W., De Jonghe, P., Van Den Bosch, L.,Janssens, S., Timmerman, V., 2010. Mutant HSPB8 causes motor neuron-specificneurite degeneration. Hum. Mol. Genet. 19, 3254–3265.

Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I., Verpoorten, N., 2004. Hotspot residue in small heat shock protein 22 causes distal motor neuropathy. Nat.Genet. 36, 597–601.

Ito, D., Suzuki, N., 2009. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 132, 8–15.

Jaffe, A.B., Hall, A., 2005. Rho GTPases: biochemistry and biology. Annu. Rev. CellDev. Biol. 21, 247–269.

Jager, S., Bucci, C., Tanida, I., Ueno, T., Kominami, E., Saftig, P., Eskelinen, E.L., 2004.Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117, 4837–4848.

Jahn, R., Scheller, R.H., 2006. SNAREs—engines for membrane fusion. Nat. Rev. CellBiol. 7, 631–643.

Jaiswal, J.K., Rivera, V.M., Simon, S.M., 2009. Exocytosis of post-Golgi vesicles isregulated by components of the endocytic machinery. Cell 137, 1308–1319.

James, D.I., Parone, P.A., Mattenberger, Y., Martinou, J.C., 2003. hFis1, a novelcomponent of the mammalian mitochondrial fission machinery. J. Biol. Chem.278, 36373–36379.

Jang, S.W., Svaren, J., 2009. Induction of myelin protein zero by early growthresponse 2 through upstream and intragenic elements. J. Biol. Chem. 284,20111–20120.

Jenkins, D., Seelow, D., Jehee, F., Perlyn, C., Alonso, L., Bueno, D., Donnai, D., Josifova,D., Josifiova, D., Mathijssen, I., Morton, J., Orstavik, K., Sweeney, E., Wall, S.,Marsh, J., Nurnberg, P., Passos-Bueno, M., Wilkie, A., 2007. RAB23 mutations inCarpenter syndrome imply an unexpected role for hedgehog signaling incranial-suture development and obesity. Am. J. Hum. Genet. 80, 1162–1170.

Jia, Y., Wu, S.L., Isenberg, J.S., Dai, S., Sipes, J.M., Field, L., Zeng, B., Bandle, R.W.,Ridnour, L.A., Wink, D.A., Ramchandran, R., Karger, B.L., Roberts, D.D., 2010.Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactionswith components of the actin and intermediate filament cytoskeleton. CellStress Chaperones 15, 165–181.

Jin, L., Williamson, A., Banerjee, S., Philipp, I., Rape, M., 2008a. Mechanism ofubiquitin-chain formation by the human anaphase-promoting complex. Cell133, 653–665.

Jin, N., Chow, C.Y., Liu, L., Zolov, S.N., Bronson, R., Davisson, M., Petersen, J.L., Zhang,Y., Park, S., Duex, J.E., Goldowitz, D., Meisler, M.H., Weisman, L.S., 2008b. VAC14nucleates a protein complex essential for the acute interconversion of PI3P andPI(3,5)P(2) in yeast and mouse. EMBO J. 27, 3221–3234.

Johansson, M., Rocha, N., Zwart, W., Jordens, I., Janssen, L., Kuijl, C., Olkkonen, V.M.,Neefjes, J., 2007. Activation of endosomal dynein motors by stepwise assemblyof Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin. J. Cell Biol.176, 459–471.

Johnston, J.A., Ward, C.L., Kopito, R.R., 1998. Aggresomes: a cellular response tomisfolded proteins. J. Cell Biol. 143, 1883–1898.

Jones, S.M., Howell, K.E., Henley, J.R., Cao, H., McNiven, M.A., 1998. Role of dynaminin the formation of transport vesicles from the trans-Golgi network. Science279, 573–577.

Jordanova, A., De Jonghe, P., Boerkoel, C.F., Takashima, H., De Vriendt, E., Ceuterick,C., Martin, J.J., Butler, I.J., Mancias, P., Papasozomenos, S.C., Terespolsky, D.,Potocki, L., Brown, C.W., Shy, M., Rita, D.A., Tournev, I., Kremensky, I., Lupski, J.R.,Timmerman, V., 2003. Mutations in the neurofilament light chain gene (NEFL)cause early onset severe Charcot–Marie–Tooth disease. Brain 126, 590–597.




G Model


Jordanova, A., Irobi, J., Thomas, F.P., Van Dijck, P., Meerschaert, K., Dewil, M., Dierick,I., Jacobs, A., De Vriendt, E., Guergueltcheva, V., Rao, C.V., Tournev, I., Gondim,F.A., D’Hooghe, M., Van Gerwen, V., Callaerts, P., Van Den Bosch, L., Timmer-mans, J.P., Robberecht, W., Gettemans, J., Thevelein, J.M., De Jonghe, P., Kre-mensky, I., Timmerman, V., 2006. Disrupted function and axonal distribution ofmutant tyrosyl-tRNA synthetase in dominant intermediate Charcot–Marie–Tooth neuropathy. Nat. Genet. 38, 197–2002.

Kabzinska, D., Drac, H., Sherman, D.L., Kostera-Pruszczyk, A., Brophy, P.J., Kochanski,A., Hausmanowa-Petrusewicz, I., 2006. Charcot–Marie–Tooth type 4F diseasecaused by S399fsx410 mutation in the PRX gene. Neurology 66, 745–747.

Kabzinska, D., Niemann, A., Drac, H., Huber, N., Potulska-Chromik, A., Hausmanowa-Petrusewicz, I., Suter, U., Kochanski, A., 2011. A new missense GDAP1 mutationdisturbing targeting to the mitochondrial membrane causes a severe form ofAR-CMT2C disease. Neurogenetics 12, 145–153.

Kachhap, S.K., Faith, D., Qian, D.Z., Shabbeer, S., Galloway, N.L., Pili, R., Denmeade,S.R., DeMarzo, A.M., Carducci, M.A., 2007. The N-Myc down regulated Gene1(NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin. PLoSONE 2, e844.

Kalaydjieva, L., Gresham, D., Gooding, R., Heather, L., Baas, F., de Jonge, R., Blechsch-midt, K., Angelicheva, D., Chandler, D., Worsley, P., Rosenthal, A., King, R.H.,Thomas, P.K., 2000. N-myc downstream-regulated gene 1 is mutated in heredi-tary motor and sensory neuropathy-Lom. Am. J. Hum. Genet. 67, 47–58.

Kalaydjieva, L., Hallmayer, J., Chandler, D., Savov, A., Nikolova, A., Angelicheva, D.,King, R.H., Ishpekova, B., Honeyman, K., Calafell, F., Shmarov, A., Petrova, J.,Turnev, I., Hristova, A., Moskov, M., Stancheva, S., Petkova, I., Bittles, A.H.,Georgieva, V., Middleton, L., Thomas, P.K., 1996. Gene mapping in Gypsiesidentifies a novel demyelinating neuropathy on chromosome 8q24. Nat. Genet.14, 214–217.

Kalaydjieva, L., Nikolova, A., Turnev, I., Petrova, J., Hristova, A., Ishpekova, B.,Petkova, I., Shmarov, A., Stancheva, S., Middleton, L., Merlini, L., Trogu, A.,Muddle, J.R., King, R.H., Thomas, P.K., 1998. Hereditary motor and sensoryneuropathy-Lom, a novel demyelinating neuropathy associated with deafnessin gypsies. Clinical, electrophysiological and nerve biopsy findings. Brain 121,399–408.

Kang-Decker, N., Cao, S., Chatterjee, S., Yao, J., Egan, L.J., Semela, D., Mukhopadhyay,D., Shah, V., 2007. Nitric oxide promotes endothelial cell survival signalingthrough S-nitrosylation and activation of dynamin-2. J. Cell Sci. 120, 492–501.

Kaplan, D., Hempstead, B., Martin-Zanca, D., Chao, M., Parada, L., 1991. The trkproto-oncogene product: a signal transducing receptor for nerve growth factor.Science 252, 554–558.

Kappe, G., Franck, E., Verschuure, P., Boelens, W.C., Leunissen, J.A., de Jong, W.W.,2003. The human genome encodes 10 a-crystallin-related small heat shockproteins: HspB1–10. Cell Stress Chaperones 8, 53–61.

Karki, S., Holzbaur, E.L., 1999. Cytoplasmic dynein and dynactin in cell division andintracellular transport. Curr. Opin. Cell Biol. 11, 45–53.

Karten, B., Peake, K.B., Vance, J.E., 2009. Mechanisms and consequences of impairedlipid trafficking in Niemann–Pick type C1-deficient mammalian cells. Biochim.Biophys. Acta 1791, 659–670.

Katzmann, D.J., Babst, M., Emr, S.D., 2001. Ubiquitin-dependent sorting into themultivesicular body pathway requires thefunction of a conservedendosomalprotein sorting complex, ESCRT-I. Cell 106, 145–155.

Kessels, M.M., Dong, J., Leibig, W., Westermann, P., Qualmann, B., 2006. Complexesof syndapin II with dynamin II promote vesicle formation at the trans-Golginetwork. J. Cell Sci. 119, 1504–1516.

Kessels, M.M., Engqvist-Goldstein, A.E., Drubin, D.G., Qualmann, B., 2001. Mamma-lian Abp1, a signal-responsive F-actin-binding protein, links the actin cytoskel-eton to endocytosis via the GTPase dynamin. J. Cell Biol. 153, 351–366.

Kijima, K., Numakura, C., Izumino, H., Umetsu, K., Nezu, A., Shiiki, T., Ogawa, M.,Ishizaki, Y., Kitamura, T., Shozawa, Y., Hayasaka, K., 2005. Mitochondrial GTPasemitofusin 2 mutation in Charcot–Marie–Tooth neuropathy type 2A. Hum.Genet. 116, 23–27.

Kijima, K., Numakura, C., Shirahata, E., Sawaishi, Y., Shimohata, M., Igarashi, S.,Tanaka, T., Hayasaka, K., 2004. Periaxin mutation causes early-onset but slow-progressive Charcot–Marie–Tooth disease. J. Hum. Genet. 49, 376–379.

Kim, M.V., Kasakov, A.S., Seit-Nebi, A.S., Marston, S.B., Gusev, N.B., 2006. Structureand properties of K141E mutant of small heat shock proteins HSP22 (HspB8,H11) that is expressed in human neuromuscular disorders. Arch. Biochem.Biophys. 454, 32–41.

Kim, M.V., Seit-Nebi, A.S., Marston, S.B., Gusev, N.B., 2004. Some properties ofhuman small heat shock protein Hsp22 (H11 or HspB8). Biochem. Biophys.Res. Commun. 315, 796–801.

Kim, S.A., Vacratsis, P.O., Firestein, R., Cleary, M.L., Dixon, J.E., 2003. Regulation ofmyotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5,a catalytically inactive phosphatase. Proc. Natl. Acad. Sci. U.S.A. 100, 4492–4497.

Kim, Y., Chang, S., 2006. Ever-expanding network of dynamin-interacting proteins.Mol. Neurobiol. 34, 129–136.

King, R.H., Chandler, D., Lopaticki, S., Huang, D., Blake, J., Muddle, J.R., Kilpatrick, T.,Nourallah, M., Miyata, T., Okuda, T., Carter, K.W., Hunter, M., Angelicheva, D.,Morahan, G., Kalaydjieva, L., 2011. Ndrg1 in development and maintenance ofthe myelin sheath. Neurobiol. Dis. 42, 368–380.

Klein, D.E., Lee, A., Frank, D.W., Marks, M.S., Lemmon, M.A., 1998. The pleckstrinhomology domains of dynamin isoforms require oligomerization for highaffinity phosphoinositide binding. J. Biol. Chem. 273, 27725–27733.

Klein, R., Jing, S., Nanduri, V., O’Rourke, E., Barbacid, M., 1991. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197.


Kobielak, A., Fuchs, E., 2004. Alpha-catenin: at the junction of intercellular adhesionand actin dynamics. Nat. Rev. Mol. Cell Biol. 5, 614–625.

Koch, A.W., Pokutta, S., Lustig, A., Engel, J., 1997. Calcium binding and homoassocia-tion of E-cadherin domains. Biochemistry 36, 7697–7705.

Koga, H., Kaushik, S., Cuervo, A.M., 2011. Protein homeostasis and aging: theimportance of exquisite quality control. Ageing Res. Rev. 10, 205–215.

Komatsu, M., Wang, Q.J., Holstein, G.R., Friedrich, V.L.J., Iwata, J., Kominami, E., Chait,B.T.K.T, Yue, Z., 2007. Essential role for autophagy protein Atg7 in the mainte-nance of axonal homeostasis and the prevention of axonal degeneration. Proc.Natl. Acad. Sci. U.S.A. 104, 14489–14494.

Koshiba, T., Detmer, S.A., Kaiser, J.T., Chen, H., McCaffery, J.M., Chan, D.C., 2004.Structural basis of mitochondrial tethering by mitofusin complexes. Science305, 858–862.

Kostenko, S., Johannessen, M., Moens, U., 2009. PKA-induced F-actin rearrangementrequires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cell. Signal. 21,712–718.

Kottgen, M., Buchholz, B., Garcia-Gonzalez, M.A., Kotsis, F., Fu, X., Doerken, M.,Boehlke, C., Steffl, D., Tauber, R., Wegierski, T., Nitschke, R., Suzuki, M., Kramer-Zucker, A., Germino, G.G., Watnick, T., Prenen, J., Nilius, B., Kuehn, E.W., Walz, G.,2008. TRPP2 and TRPV4 form a polymodal sensory channel complex. J. Cell Biol.182, 437–447.

Krajewski, K.M., Lewis, R.A., Fuerst, D.R., Turansky, C., Hinderer, S.R., Garbern, J.,Kamholz, J., Shy, M.E., 2000. Neurological dysfunction and axonal degenerationin Charcot–Marie–Tooth disease type 1A. Brain 123, 1516–1527.

Kramer, E.M., Schardt, A., Nave, K.A., 2001. Membrane traffic in myelinatingoligodendrocytes. Microsc. Res. Tech. 52, 656–671.

Kreitzer, G., Marmorstein, A., Okamoto, P., Vallee, R., Rodriguez-Boulan, E., 2000.Kinesin and dynamin are required for post-Golgi transport of a plasma-mem-brane protein. Nat. Cell Biol. 2, 125–127.

Krueger, E.W., Orth, J.D., Cao, H., McNiven, M.A., 2003. A dynamin-cortactin-Arp2/3complex mediates actin reorganization in growth factor-stimulated cells. Mol.Biol. Cell 14, 1085–1096.

Kurdistani, S.K., Arizti, P., Reimer, C.L., Sugrue, M.M., Aaronson, S.A., Lee, S.W., 1998.Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 andDNA damage. Cancer Res. 58, 4439–4444.

Kutateladze, T.G., 2006. Phosphatidylinositol 3-phosphate recognition and mem-brane docking by the FYVE domain. Biochim. Biophys. Acta 1761, 868–877.

Lachat, P., Shaw, P., Gebhard, S., van Belzen, N., Chaubert, P., Bosman, F.T., 2002.Expression of NDRG1, a differentiation-related gene, in human tissues. Histo-chem. Cell Biol. 118, 399–408.

Landoure, G., Zdebik, A.A., Martinez, T.L., Burnett, B.G., Stanescu, H.C., Inada, H., Shi,Y., Taye, A.A., Kong, L., Munns, C.H., Choo, S.S., Phelps, C.B., Paudel, R., Houlden,H., Ludlow, C.L., Caterina, M.J., Gaudet, R., Kleta, R., Fischbeck, K.H., Sumner, C.J.,2010. Mutations in TRPV4 cause Charcot–Marie–Tooth disease type 2C. Nat.Genet. 42, 170–174.

Laporte, J., Liaubet, L., Blondeau, F., Tronchere, H., Mandel, J.L., Payrastre, B., 2002.Functional redundancy in the myotubularin family. Biochem. Biophys. Res.Commun. 291, 305–312.

Latour, P., Gonnaud, P.-M., Ollagnon, E., Chan, V., Perelman, S., Stojkovic, T., Stoll, C.,Vial, C., Ziegler, F., Vandenberghe, A., Maire, I., 2006. SIMPLE mutation analysisin dominant demyelinating Charcot–Marie–Tooth disease: three novel muta-tions. J. Peripher. Nerv. Syst. 11, 148–155.

Latour, P., Thauvin-Robinet, C., Baudelet-Mery, C., Soichot, P., Cusin, V., Faivre, L.,Locatelli, M.C., Mayencon, M., Sarcey, A., Broussolle, E., Camu, W., David, A.,Rousson, R., 2010. A major determinant for binding and aminoacylation oftRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominantaxonal Charcot–Marie–Tooth disease. Am. J. Hum. Genet. 86, 77–82.

Lavoie, J.N., Hickey, E., Weber, L.A., Landry, J., 1993. Modulation of actin microfila-ment dynamics and fluid phase pinocytosis by phosphorylation of heat shockprotein 27. J. Biol. Chem. 268, 24210–24214.

Lawson, V.H., Graham, B.V., Flanigan, K.M., 2005. Clinical and electrophysiologicfeatures of CMT2A with mutations in the mitofusin 2 gene. Neurology 65, 197–204.

Le, T.L., Yap, A.S., Stow, J.L., 1999. Recycling of E-cadherin: a potential mechanism forregulating cadherin dynamics. J. Cell Biol. 146, 219–232.

Leal, A., Huehne, K., Bauer, F., Sticht, H., Berger, P., Suter, U., Morera, B., Del Valle, G.,Lupski, J.R., Ekici, A., Pasutto, F., Endele, S., Barrantes, R., Berghoff, C., Berghoff,M., Neundorfer, B., Heuss, D., Dorn, T., Young, P., Santolin, L., Uhlmann, T.,Meisterernst, M., Sereda, M.W., Stassart, R.M., Zu Horste, G.M., Nave, K.A., Reis,A., Rautenstrauss, B., 2009. Identification of the variant Ala335Val of MED25 asresponsible for CMT2B2: molecular data, functional studies of the SH3 recog-nition motif and correlation between wild-type MED25 and PMP22 RNA levelsin CMT1A animal models. Neurogenetics 10, 275–287.

Lee, H.W., Kim, Y., Han, K., Kim, H., Kim, E., 2010. The phosphoinositide 3-phospha-tase MTMR2 interacts with PSD-95 and maintains excitatory synapses bymodulating endosomal traffic. J. Neurosci. 30, 5508–5518.

Lee, J.W., Kwak, H.J., Lee, J.J., Kim, Y.N., Lee, J.W., Park, M.J., Jung, S.E., Hong, S.I., Lee,J.H., Lee, J.S., 2008. HSP27 regulates cell adhesion and invasion via modulation offocal adhesion kinase and MMP-2 expression. Eur. J. Cell Biol. 87, 377–387.

Lee, M.J., Lee, B.H., Hanna, J., King, R.W., Finley, D., 2011a. Trimming of ubiquitinchains by proteasome-associated deubiquitinating enzymes. Mol. Cell. Proteo-mics 10 R110.003871.

Lee, S.M., Olzmann, J.A., Chin, L.-S., Li, L., 2011b. Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation bythe proteasome and aggresome–autophagy pathways. J. Cell Sci. 124, 3319–3331.




G Model


Legros, F., Lombes, A., Frachon, P., Rojo, M., 2002. Mitochondrial fusion in humancells is efficient, requires the inner membrane potential, and is mediated bymitofusins. Mol. Biol. Cell 13, 4343–4354.

Lemmon, M.A., 2008. Membrane recognition by phospholipid-binding domains.Nat. Rev. Mol. Cell Biol. 9, 99–111.

Levy, J.R., Holzbaur, E.L., 2006. Cytoplasmic dynein/dynactin function and dysfunc-tion in motor neurons. Int. J. Dev. Neurosci. 24, 103–111.

Lewallen, K.A., Shen, Y.A., De La Torre, A.R., Ng, B.K., Meijer, D., Chan, J.R., 2011.Assessing the role of the cadherin/catenin complex at the schwann cell-axoninterface and in the initiation of myelination. J. Neurosci. 31, 3032–3043.

Li, B., Smith, C.C., Laing, J.M., Gober, M.D., Liu, L., Aurelian, L., 2007. Overload of theheat-shock protein H11/HspB8 triggers melanoma cell apoptosis through acti-vation of transforming growth factor-beta-activated kinase 1. Oncogene 26,3521–3531.

Li, B., Su, Y., Ryder, J., Yan, L., Na, S., Ni, B., 2003. RIFLE: a novel ring zinc finger-leucine-rich repeat containing protein, regulates select cell adhesion moleculesin PC12 cells. J. Cell. Biochem. 90, 1224–1241.

Li, X., Sapp, E., Valencia, A., Kegel, K.B., Qin, Z.H., Alexander, J., Masso, N., Reeves, P.,Ritch, J.J., Zeitlin, S., Aronin, N., Difiglia, M., 2008. A function of huntingtin inguanine nucleotide exchange on Rab11. Neuroreport 19.

Li, X., Valencia, A., Sapp, E., Masso, N., Alexander, J., Reeves, P., Kegel, K.B., Aronin, N.,Difiglia, M., 2010. Aberrant Rab11-dependent trafficking of the neuronal gluta-mate transporter EAAC1 causes oxidative stress and cell death in Huntington’sdisease. J. Neurosci. 30, 4552–4561.

Li, Y., Lim, S., Hoffman, D., Aspenstrom, P., Federoff, H.J., Rempe, D.A., 2009. HUMMR,a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial distributionand transport. J. Cell Biol. 185, 1065–1081.

Liem, R.K., 1993. Molecular biology of neuronal intermediate filaments. Curr. Opin.Cell Biol. 5, 12–16.

Lin, H., Schlaepfer, W.W., 2006. Role of neurofilament aggregation in motor neurondisease. Ann. Neurol. 60, 399–406.

Lin, H.C., Barylko, B., Achiriloaie, M., Albanesi, J.P., 1997. Phosphatidylinositol (4, 5)-bisphosphate-dependent activation of dynamins I and II lacking the proline/arginine-rich domains. J. Biol. Chem. 272, 25999–26004.

Lindmo, K., Stenmark, H., 2006. Regulation of membrane traffic by phosphoinositide3-kinases. J. Cell Sci. 605–614.

Lipschutz, J.H., Guo, W., O’Brien, L.E., Nguyen, Y.H., Novick, P., Mostov, K.E., 2000.Exocyst is involved in cystogenesis and tubulogenesis and acts by modulatingsynthesis and delivery of basolateral plasma membrane and secretory proteins.Mol. Biol. Cell 11, 4259–4275.

Liu, R.-Y., Snider, W.D., 2001. Different signaling pathways mediate regenerativeversus developmental sensory axon growth. J. Neurosci. 21, RC164.

Liu, Y., Bankaitis, V.A., 2010. Phosphoinositide phosphatases in cell biology anddisease. Prog. Lipid Res. 49, 201–217.

Liu, Y.W., Surka, M.C., Schroeter, T., Lukiyanchuk, V., Schmid, S.L., 2008. Isoform andsplice-variant specific functions of dynamin-2 revealed by analysis of condi-tional knock-out cells. Mol. Biol. Cell 19, 5347–5359.

Lobsiger, C.S., Cleveland, D.W., 2007. Glial cells as intrinsic components of non-cellautonomous neurodegenerative disease. Nat. Neurosci. 10, 1355–1360.

Loerke, D., Mettlen, M., Yarar, D., Jaqaman, K., Jaqaman, H., Danuser, G., Schmid, S.L.,2009. Cargo and dynamin regulate clathrin-coated pit maturation. PLoS Biol. 7,e57.

Lumb, J.H., Field, M.F., 2010. Rab28 mediates trafficking at the multivesicular body.Mol. Biol. Cell 21 (Suppl.), 1264 Abs.

Luna, A., Matas, O.B., Martınez-Menarguez, J.A., Mato, E., Duran, J.M., Ballesta, J.,Way, M., Egea, G., 2002. Regulation of protein transport from the Golgi complexto the endoplasmic reticulum by CDC42 and N-WASP. Mol. Biol. Cell 13, 866–879.

Lundmark, R., Carlsson, S.R., 2004. Regulated membrane recruitment of dynamin-2mediated by sorting nexin 9. J. Biol. Chem. 279, 42694–42702.

Lundmark, R., Carlsson, S.R., 2005. Expression and properties of sorting nexin 9 indynamin-mediated endocytosis. Methods Enzymol. 404, 545–556.

Lupski, J.R., de Oca-Luna, R.M., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B.J.,Saucedo-Cardenas, O., Barker, D.F., Killian, J.M., Garcia, C.A., Chakravarti, A.,Patel, P.I., 1991. DNA duplication associated with Charcot–Marie–Tooth diseasetype 1A. Cell 66, 219–232.

Lyons, D.A., Naylor, S.G., Scholze, A., Talbot, W.S., 2009. Kif1b is essential for mRNAlocalization in oligodendrocytes and development of myelinated axons. Nat.Genet. 41, 854–858.

Maier, O., Hoekstra, D., Baron, W., 2008. Polarity development in oligodendrocytes:sorting and trafficking of myelin components. J. Mol. Neurosci. 35, 35–53.

Maier, O., Knoblich, M., Westermann, P., 1996. Dynamin II binds to the trans-Golginetwork. Biochem. Biophys. Res. Commun. 223, 229–233.

Mallik, R., Gross, S.P., 2004. Molecular motors: strategies to get along. Curr. Biol. 14,R971–R982.

Marat, A.L., Dokainish, H., McPherson, P.S., 2011. DENN domain proteins: regulatorsof Rab GTPases. J. Biol. Chem. 286, 13791–13800.

Marat, A.L., McPherson, P.S., 2010. The connecdenn family, Rab35 guanine nucleo-tide exchange factors interfacing with the clathrin machinery. J. Biol. Chem.285, 10627–10637.

Marchesi, C., Milani, M., Morbin, M., Cesani, M., Lauria, G., Scaioli, V., Piccolo, G.,Fabrizi, G.M., Cavallaro, T., Taroni, F., Pareyson, D., 2010. Four novel cases ofperiaxin-related neuropathy and review of the literature. Neurology 75, 1830–1838.

Markgraf, D.F., Peplowska, K., Ungermann, C., 2007. Rab cascades and tetheringfactors in the endomembrane system. FEBS Lett. 581, 2125–2130.


Marks, M.S., 2008. FIG4, Charcot–Marie–Tooth disease, and hypopigmentation: arole for phosphoinositides in melanosome biogenesis? Pigment Cell MelanomaRes. 21, 11–14.

Martinez-Vicente, M., Cuervo, A.M., 2007. Autophagy and neurodegeneration:when the cleaning crew goes on strike. Lancet Neurol. 6, 352–361.

Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries,R., Arias, E., Harris, S., Sulzer, D., Cuervo, A.M., 2010. Cargo recognition failure isresponsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 13,567–576.

Matas, O.B., Martınez-Menarguez, J.A., Egea, G., 2004. Association of Cdc42/N-WASP/Arp2/3 signaling pathway with Golgi membranes. Traffic 5, 838–846.

Matsunami, N., Smith, B., Ballard, L., Lensch, M.W., Robertson, M., Albertsen, H.,Hanemann, C.O., Muller, H.W., Bird, T.D., White, R., Chance, P.F., 1992. Peripheralmyelin protein-22 gene maps in the duplication in chromosome 17p11.2associated with Charcot–Marie–Tooth 1A. Nat. Genet. 1, 176–179.

McCray, B.A., Skordalakes, E., Taylor, J.P., 2010. Disease mutations in Rab7 result inunregulated nucleotide exchange and inappropriate activation. Hum. Mol.Genet. 19, 1033–1047.

McDonald, B., Martin-Serrano, J., 2008. Regulation of Tsg101 expression by thesteadiness box: a role of Tsg101-associated ligase. Mol. Biol. Cell 19, 754–763.

McNiven, M.A., Kim, L., Krueger, E.W., Orth, J.D., Cao, H., Wong, T.W., 2000.Regulated interactions between dynamin and the actin-binding protein cor-tactin modulate cell shape. J. Cell Biol. 151, 187–198.

McPherson, P.S., 1999. Regulatory role of SH3 domain-mediated protein-proteininteractions in synaptic vesicle endocytosis. Cell. Signal. 11, 229–238.

Meggouh, F., Bienfait, H.M., Weterman, M.A., de Visser, M., Baas, F., 2006. Charcot–Marie–Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67,1476–1478.

Mehlen, P., Mehlen, A., Godet, J., Arrigo, A.P., 1997. hsp27 as a switch betweendifferentiation and apoptosis in murine embryonic stem cells. J. Biol. Chem. 272,31657–31665.

Melotte, V., Qu, X., Ongenaert, M., van Criekinge, W., de Bruıne, A.P., Baldwin, H.S.,van Engeland, M., 2010. The N-myc downstream regulated gene (NDRG) family:diverse functions, multiple applications. FASEB J. 24, 4153–4166.

Merino-Gracia, J., Garcıa-Mayoral, M.F., Rodrıguez-Crespo, I., 2011. The associationof viral proteins with host cell dynein components during virus infection. FEBS J.278, 2997–3011.

Mersiyanova, I.V., Perepelov, A.V., Polyakov, A.V., Sitnikov, V.F., Dadali, E.L., Oparin,R.B., Petrin, A.N., Evgrafov, O.V., 2000. A new variant of Charcot–Marie–Toothdisease type 2 is probably the result of a mutation in the neurofilament lightgene. Am. J. Hum. Genet. 67, 37–46.

Michell, R.H., Dove, S.K., 2009. A protein complex that regulates PtdIns(3,5)P2levels. EMBO J. 28, 86–87.

Michell, R.H., Heath, V.L., Lemmon, M.A., Dove, S.K., 2006. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63.

Mikesova, E., Huhne, K., Rautenstrauss, B., Mazanec, R., Barankova, L., Vyhnalek,M., Horacek, O., Seeman, P., 2005. Novel EGR2 mutation R359Q is associatedwith CMT type 1 and progressive scoliosis. Neuromuscul. Disord. 15, 764–767.

Min, L., Leung, Y.M., Tomas, A., Watson, R.T., Gaisano, H.Y., Halban, P.A., Pessin, J.E.,Hou, J.C., 2007. Dynamin is functionally coupled to insulin granule exocytosis. J.Biol. Chem. 282, 33530–33536.

Minin, A.A., Moldaver, M.N., 2008. Intermediate vimentin filaments and their role inintracellular organelle distribution. Biochemistry (Mosc) 73, 1453–1466.

Mir, A., Kaufman, L., Noor, A., Motazacker, M., Jamil, T., Azam, M., Kahrizi, K., Rafiq,M., Weksberg, R., Nasr, T., Naeem, F., Tzschach, A.A.K., Ishak, G., Doherty, D.,Ropers, H., Barkovich, A., Najmabadi, H., Ayub, M., Vincent, J., 2009. Identifica-tion of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-bindingprotein, in nonsyndromic autosomal-recessive mental retardation. Am. J. Hum.Genet. 85, 909–915.

Misko, A., Jiang, S., Wegorzewska, I., Milbrandt, J., Baloh, R.H., 2010. Mitofusin 2 isnecessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J. Neurosci. 30, 4232–4240.

Mitra, S., Cheng, K.W., Mills, G.B., 2011. Rab GTPases implicated in inherited andacquired disorders. Semin. Cell Dev. Biol. 22, 57–68.

Mochida, G., Mahajnah, M., Hill, A., Basel-Vanagaite, L., Gleason, D., Hill, R., Bodell,A., Crosier, M., Straussberg, R., Walsh, C., 2009. A truncating mutation ofTRAPPC9 is associated with autosomal recessive intellectual disability andpostnatal microcephaly. Am. J. Hum. Genet. 85, 897–902.

Mohl, M., Winkler, S., Wieland, T., Lutz, S., 2006. Gef10—the third member of a Rho-specific guanine nucleotide exchange factor subfamily with unusual proteinarchitecture. Naunyn. Schmiedebergs Arch. Pharmacol. 373, 333–341.

Mollapour, M., Phelan, J.P., Millson, S.H., Piper, P.W., Cooke, F.T., 2006. Weak acidand alkali stress regulate phosphatidylinositol bisphosphate synthesis in Sac-charomyces cerevisiae. Biochem. J. 395, 73–80.

Momboisse, F., Ory, S., Calco, V., Malacombe, M., Bader, M.F., Gasman, S., 2009.Calcium-regulated exocytosis in neuroendocrine cells: intersectin-1L stimu-lates actin polymerization and exocytosis by activating Cdc42. Ann. N. Y. Acad.Sci. 1152, 209–214.

Mooren, O.L., Kotova, T.I., Moore, A.J., Schafer, D.A., 2009. Dynamin2 GTPase andcortactin remodel actin filaments. J. Biol. Chem. 284, 23995–24005.

Morfini, G.A., Burns, M., Binder, L.I., Kanaan, N.M., LaPointe, N., Bosco, D.A., Brown Jr.,R.H., Brown, H., Tiwari, A., Hayward, L., Edgar, J., Nave, K.A., Garberrn, J., Atagi, Y.,Song, Y., Pigino, G., Brady, S.T., 2009. Axonal transport defects in neurodegen-erative diseases. J. Neurosci. 29, 12776–12786.




G Model


Moriwaki, Y., Begum, N.A., Kobayashi, M., Matsumoto, M., Toyoshima, K., Seya, T.,2001. Mycobacterium bovis Bacillus Calmette-Guerin and its cell wall complexinduce a novel lysosomal membrane protein, SIMPLE, that bridges the missinglink between lipopolysaccharide and p53-inducible gene, LITAF(PIG7), andestrogen-inducible gene, EET-1. J. Biol. Chem. 276, 23065–23076.

Mounier, N., Arrigo, A.P., 2002. Actin cytoskeleton and small heat shock proteins:how do they interact? Cell Stress Chaperones 7, 167–176.

Mruk, D.D., Lau, A.S., Sarkar, O., Xia, W., 2007. Rab4A GTPase catenin interactions areinvolved in cell junction dynamics in the testis. J. Androl. 28, 742–754.

Mundigl, O., Ochoa, G.C., David, C., Slepnev, V.I., Kabanov, A., De Camilli, P., 1998.Amphiphysin I antisense oligonucleotides inhibit neurite outgrowth in culturedhippocampal neurons. J. Neurosci. 18, 93–103.

Munirajan, A.K., Ando, K., Mukai, A., Takahashi, M., Suenaga, Y., Ohira, M., Koda, T.,Hirota, T.T.O., Nakagawara, A., 2008. KIF1Bbeta functions as a haploinsufficienttumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptoticcell death. J. Biol. Chem. 283, 24426–24434.

Musch, A., Cohen, D., Kreitzer, G., Rodriguez-Boulan, E., 2001. Cdc42 regulates theexit of apical and basolateral proteins from the trans-Golgi network. EMBO J. 20,2171–2179.

Musso, M., Balestra, P., Bellone, E., Cassandrini, D., Di Maria, E., Doria, L.L., Grandis,M., Mancardi, G.L., Schenone, A., Levi, G., Ajmar, F., Mandich, P., 2001. The D355Vmutation decreases EGR2 binding to an element within the Cx32 promoter.Neurobiol. Dis. 8, 700–706.

Musumeci, O., Bassi, M.T., Mazzeo, A., Grandis, M., Crimella, C., Martinuzzi, A.,Toscano, A., 2011. A novel mutation in KIF5A gene causing hereditary spasticparaplegia with axonal neuropathy. Neurol. Sci. 32, 665–668.

Naef, R., Suter, U., 1998. Many facets of the peripheral myelin protein PMP22 inmyelination and disease. Microsc. Res. Tech. 41, 359–371.

Nagai, M., Re, D.B., Nagata, T., Chalazonitis, A., Jessell, T.M., Wichterle, H., Przed-borski, S., 2007. Astrocytes expressing ALS-linked mutated SOD1 release factorsselectively toxic to motor neurons. Nat. Neurosci. 10, 615–622.

Nagar, B., Overduin, M., Ikura, M., Rini, J.M., 1996. Structural basis of calcium-induced E-cadherin rigidification and dimerization. Nature 380, 360–364.

Nagarajan, R., Svaren, J., Le, N., Araki, T., Watson, M., Milbrandt, J., 2001. EGR2mutations in inherited neuropathies dominant-negatively inhibit myelin geneexpression. Neuon 30, 355–368.

Nakanishi, H., Takai, Y., 2008. Frabin and other related Cdc42-specific guaninenucleotide exchange factors couple the actin cytoskeleton with the plasmamembrane. J. Cell. Mol. Med. 12, 1169–1176.

Naughtin, M.J., Sheffield, D.A., Rahman, P., Hughes, W.E., Gurung, R., Stow, J.L.,Nandurkar, H.H., Dyson, J.M., Mitchell, C.A., 2010. The myotubularin phospha-tase MTMR4 regulates sorting from early endosomes. J. Cell Sci. 123, 3071–3083.

Nave, K.A., 2010. Myelination and support of axonal integrity by glia. Nature 468,244–252.

Neuberg, D.H., Suter, U., 1999. Connexin32 in hereditary neuropathies. Adv. Exp.Med. Biol. 468, 227–236.

Ng, D.S., O’Connor, P.W., Mortimer, C.B., Leiter, L.A., Connelly, P.W., Hegele, R.A.,1996. Case report: retinopathy and neuropathy associated with completeapolipoprotein A-I deficiency. Am. J. Med. Sci. 312, 30–33.

Nicot, A.S., Laporte, J., 2008. Endosomal phosphoinositides and human diseases.Traffic 9, 1240–1249.

Niemann, A., Berger, P., Suter, U., 2006. Pathomechanisms of mutant proteins inCharcot–Marie–Tooth disease. Neuromol. Med. 8, 217–242.

Niemann, A., Ruegg, M., La Padula, V., Schenone, A., Suter, U., 2005. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrialnetwork: new implications for Charcot–Marie–Tooth disease. J. Cell Biol. 170,1067–1078.

Niemann, A., Wagner, K.M., Ruegg, M., Suter, U., 2009. GDAP1 mutations differ intheir effects on mitochondrial dynamics and apoptosis depending on the modeof inheritance. Neurobiol. Dis. 36, 509–520.

Niwa, S., Tanaka, Y., Hirokawa, N., 2008. KIF1Bbeta- and KIF1A-mediated axonaltransport of presynaptic regulator Rab3 occurs in a GTP-dependent mannerthrough DENN/MADD. Nat. Cell Biol. 10, 1269–1279.

Obaishi, H., Nakanishi, H., Mandai, K., Satoh, K., Satoh, A., Takahashi, K., Miyahara,M., Nishioka, H., Takaishi, K., Takai, Y., 1998. Frabin, a novel FGD1-related actinfilament-binding protein capable of changing cell shape and activating c-Jun N-terminal kinase. J. Biol. Chem. 273, 18697–18700.

Ochoa, G.C., Slepnev, V.I., Neff, L., Ringstad, N., Takei, K., Daniell, L., Kim, W., Cao, H.,McNiven, M., Baron, R., De Camilli, P., 2000. A functional link between dynaminand the actin cytoskeleton at podosomes. J. Cell Biol. 150, 377–389.

Odorizzi, G., Babst, M., Emr, S.D., 1998. Fab1p PtdIns(3)P 5-kinase function essentialfor protein sorting in the multivesicular body. Cell 95, 847–858.

Okuda, T., Higashi, Y., Kokame, K., Tanaka, C., Kondoh, H., Miyata, T., 2004. Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheralnerves. Mol. Cell. Biol. 24, 3949–3956.

Olichon, A., Emorine, L.J., Descoins, E., Pelloquin, L., Brichese, L., Gas, N., Guillou, E.,Delettre, C., Valette, A., Hamel, C.P., Ducommun, B., Lenaers, G., Belenguer, P.,2002. The human dynamin-related protein OPA1 is anchored to the mitochon-drial inner membrane facing the inter-membrane space. FEBS Lett. 523, 171–176.

Olkkonen, V.M., Ikonen, E., 2000. Genetic defects of intracellular-membrane trans-port. N. Engl. J. Med. 343, 1095–1104.

Olkkonen, V.M., Ikonen, E., 2006. When intracellular logistics fails—genetic defectsin membrane trafficking. J. Cell Sci. 119, 5031–5045.


Ono, Y., Nakanishi, H., Nishimura, M., Kakizaki, M., Takahashi, K., Miyahara, M.,Satoh-Horikawa, K., Mandai, K., Takai, Y., 2000. Two actions of frabin: directactivation of Cdc42 and indirect activation of Rac. Oncogene 19, 3050–3058.

Pal, A., Severin, F., Lommer, B., Shevchenko, A., Zerial, M., 2006. Huntingtin–HAP40complex is a novel Rab5 effector that regulates early endosome motility and isup-regulated in Huntington’s disease. J. Cell Biol. 172, 605–618.

Pankiv, S., Alemu, E.A., Brech, A., Bruun, J.A., Lamark, T., Overvatn, A., Bjørkøy, G.,Johansen, T., 2010. FYCO1 is a Rab7 effector that binds to LC3 and PI3P tomediate microtubule plus end-directed vesicle transport. J. Cell Biol. 188, 253–269.

Parcellier, A., Brunet, M., Schmitt, E., Col, E., Didelot, C., Hammann, A., Nakayama, K.,Nakayama, K.I., Khochbin, S., Solary, E., Garrido, C., 2006. HSP27 favors ubiqui-tination and proteasomal degradation of p27Kip1 and helps S-phase re-entry instressed cells. FASEB J. 20, 1179–1181.

Parcellier, A., Schmitt, E., Gurbuxani, S., Seigneurin-Berny, D., Pance, A., Chantome,A., 2003. HSP27 is a ubiquitin-binding protein involved in I-kappaBalphaproteasomal degradation. Mol. Cell. Biol. 23, 5790–5802.

Pareyson, D., Marchesi, C., 2009. Diagnosis, natural history, and management ofCharcot–Marie–Tooth disease. Lancet Neurol. 8, 654–667.

Pareyson, D., Reilly, M.M., Schenone, A., Fabrizi, G.M., Cavallaro, T., Santoro, L., Vita,G., Quattrone, A., Padua, L., Gemignani, F., Visioli, F., Laura, M., Radice, D.,Calabrese, D., Hughes, R.A., Solari, A., 2011. Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind random-ised trial. Lancet Neurol. 10, 320–328.

Pareyson, D., Scaioli, V., Laura, M., 2006. Clinical and electrophysiological aspects ofCharcot–Marie–Tooth disease. Neuromol. Med. 8, 3–22.

Park, S.G., Kim, H.J., Min, Y.H., Choi, E.C., Shin, Y.K., Park, B.J., Lee, S.W., Kim, S., 2005.Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response.Proc. Natl. Acad. Sci. U.S.A. 102, 6356–6361.

Park, S.J., Kim, S.H., Choi, H.S., Rhee, Y., Lim, S.K., 2009. Fibroblast growth factor 2-induced cytoplasmic asparaginyl-tRNA synthetase promotes survival ofosteoblasts by regulating anti-apoptotic PI3K/Akt signaling. Bone 45, 994–1003.

Parman, Y., Battaloglu, E., Baris, I., Bilir, B., Poyraz, M., Bissar-Tadmouri, N., Williams,A., Ammar, N., Nelis, E., Timmerman, V., De Jonghe, P., Najafov, A., Deymeer, F.,Serdaroglu, P., Brophy, P.J., Said, G., 2004. Clinicopathological and genetic studyof early-onset demyelinating neuropathy. Brain 127, 2540–2550.

Passage, E., Norreel, J.C., Noack-Fraissignes, P., Sanguedolce, V., Pizant, J., Thirion, X.,Robaglia-Schlupp, A., Pellissier, J.F., Fontes, M., 2004. Ascorbic acid treatmentcorrects the phenotype of a mouse model of Charcot–Marie–Tooth disease. Nat.Med. 10, 396–401.

Patel, P., Roa, B.B., Welcher, A.A., Schoener-Scott, R., Trask, B.J., Pentao, L., Snipes, G.J.,Garcia, C.A., Francke, U., Shooter, E.M., Lupski, J.R., Suter, U., 1992. The gene forthe peripheral myelin protein PMP-22 is a candidate for Charcot–Marie–Toothdisease type 1A. Nat. Genet. 1, 159–165.

Patzko, A., Shy, M.E., 2011. Update on Charcot–Marie–Tooth disease. Curr. Neurol.Neurosci. Rep. 11, 78–88.

Pazour, G.J., Dickert, B.L., Witman, G.B., 1999. The DHC1b (DHC2) isoform ofcytoplasmic dynein is required for flagellar assembly. J. Cell Biol. 144, 473–481.

Pedrola, L., Espert, A., Valdes-Sanchez, T., Sanchez-Piris, M., Sirkowski, E.E., Scherer,S.S., Farinas, I., Palau, F., 2008. Cell expression of GDAP1 in the nervous systemand pathogenesis of Charcot–Marie–Tooth type 4A disease. J. Cell. Mol. Med. 12,679–689.

Pedrola, L., Espert, A., Wu, X., Claramunt, R., Shy, M.E., Palau, F., 2005. GDAP1, theprotein causing Charcot–Marie–Tooth disease type 4A, is expressed in neuronsand is associated with mitochondria. Hum. Mol. Genet. 14, 1087–1094.

Perez-Olle, R., Leung, C.L., Liem, R.K., 2002. Effects of Charcot–Marie–Tooth-linkedmutations of the neurofilament light subunit on intermediate filament forma-tion. J. Cell Sci. 115, 4937–4946.

Perez-Olle, R., Lopez-Toledano, M.A., Goryunov, D., Cabrera-Poch, N., Stefanis, L.,Brown, K., Liem, R.K., 2005. Mutations in the neurofilament light gene linked toCharcot–Marie–Tooth disease cause defects in transport. J. Neurochem. 93,861–874.

Perlson, E., Hanz, S., Medzihradszky, K.F., Burlingame, A.L., Fainzilber, M., 2004.From snails to sciatic nerve: Retrograde injury signaling from axon to soma inlesioned neurons. J. Neurobiol. 58, 287–294.

Perng, M.D., Cairns, L., van den IJssel, P., Prescott, A., Hutcheson, A.M., Quinlan, R.A.,1999. Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J. Cell Sci. 112, 2099–2112.

Petiot, A., Ogier-Denis, E., Blommaart, E.F.C., Meijer, A.J., Codogno, P., 2000. Distinctclasses of phosphatidylinositol 30-kinases are involved in signaling pathwaysthat control macroautophagy in HT-29 cells. J. Biol. Chem. 275, 992–998.

Pfeffer, S.R., 1999. Transport-vesicle targeting: tethers before SNAREs. Nat. Cell Biol.1, E17–E22.

Pfister, K.K., Fisher, E.M., Gibbons, I.R., Hays, T.S., Holzbaur, E.L., McIntosh, J.R.,Porter, M.E., Schroer, T.A., Vaughan, K.T., Witman, G.B., King, S.M., Vallee, R.B.,2005. Cytoplasmic dynein nomenclature. J. Cell Biol. 171, 411–413.

Pichon, S., Bryckaert, M., Berrou, E., 2004. Control of actin dynamics by p38 MAPkinase – Hsp27 distribution in the lamellipodium of smooth muscle cells. J. CellSci. 117, 2569–2577.

Piepenhagen, P.A., Nelson, W.J., 1993. Defining E-cadherin-associated protein com-plexes in epithelial cells: plakoglobin, beta- and gamma-catenin are distinctcomponents. J. Cell Sci. 104, 751–762.

Pitts, K.R., Yoon, Y., Krueger, E.W., McNiven, M.A., 1999. The dynamin-like proteinDLP1 is essential for normal distribution and morphology of the endoplasmicreticulum and mitochondria in mammalian cells. Mol. Biol. Cell 10, 4403–4417.




G Model


Pivovarova, A.V., Chebotareva, N.A., Chernik, I.S., Gusev, N.B., Levitsky, D.I., 2007.Small heat shock protein Hsp27 prevents heat-induced aggregation of F-actinby forming soluble complexes with denatured actin. FEBS J. 274, 5937–5948.

Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W., Vogelstein, B., 1997. A model for p53-induced apoptosis. Nature 389, 300–305.

Praefcke, G.J., McMahon, H.T., 2004. The dynamin superfamily: universal membranetubulation and fission molecules? Nat. Rev. Mol. Cell Biol. 5, 133–147.

Predescu, S.A., Predescu, D.N., Timblin, B.K., Stan, R.V., Malik, A.B., 2003. Intersectinregulates fission and internalization of caveolae in endothelial cells. Mol. Biol.Cell 14, 4997–5010.

Previtali, S.C., Quattrini, A., Bolino, A., 2007. Charcot–Marie–Tooth type 4B demye-linating neuropathy: deciphering the role of MTMR phosphatases. Expert Rev.Mol. Med. 9, 1–16.

Previtali, S.C., Zerega, B., Sherman, D.L., Brophy, P.J., Dina, G., King, R.H., Salih, M.M.,Feltri, L., Quattrini, A., Ravazzolo, R., Wrabetz, L., Monaco, A.P., Bolino, A., 2003.Myotubularin-related 2 protein phosphatase and neurofilament light chainprotein, both mutated in CMT neuropathies, interact in peripheral nerve.Hum. Mol. Genet. 12, 1713–1723.

Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J.E., Baas, F.,Barker, D.F., Martin, J.J., De Visser, M., Bolhuis, P.A., Group, V.B.a.H.C.R., 1991.Duplication in chromosome 17p11.2 in Charcot–Marie–Tooth neuropathy type1a (CMT 1a). Neuromuscul. Disord. 1, 93–97.

Rahman, S., Carlile, G., Evans, W.H., 1993. Assembly of hepatic gap junctions.Topography and distribution of connexin 32 in intracellular and plasma mem-branes determined using sequence-specific antibodies. J. Biol. Chem. 268,1260–1265.

Raiborg, C., Bremnes, B., Mehlum, A., Gillooly, D.J., D’Arrigo, A., Stang, E., Stenmark,H., 2001. FYVE and coiled-coil domains determine the specific localisation ofHrs to early endosomes. J. Cell Sci. 114, 2255–2263.

Raiborg, C., Stenmark, H., 2009. The ESCRT machinery in endosomal sorting ofubiquitylated membrane proteins. Nature 458, 445–452.

Raivich, G., Makwana, M., 2007. The making of successful axonal regeneration:genes, molecules and signal transduction pathways. Brain Res. Rev. 53, 287–311.

Rana, R., Surapureddi, S., Kam, W., Ferguson, S., Goldstein, J.A., 2011. Med25 isrequired for RNA polymerase II recruitment to specific promoters, thus regu-lating xenobiotic and lipid metabolism in human liver. Mol. Cell. Biol. 31, 466–481.

Rappoport, J.Z., Simon, S.M., 2003. Real-time analysis of clathrin-mediated endocy-tosis during cell migration. J. Cell Sci. 116, 847–855.

Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., Berger, Z., Vacher, C., O’Kane, C.J.,Brown, S.D., Rubinsztein, D.C., 2005. Dynein mutations impair autophagicclearance of aggregate-prone proteins. Nat. Genet. 37.

Read, D.E., Gorman, A.M., 2009. Heat shock protein 27 in neuronal survival andneurite outgrowth. Biochem. Biophys. Res. Commun. 382, 6–8.

Reddy, P.H., Reddy, T.P., Manczak, M., Calkins, M.J., Shirendeb, U., Mao, P., 2011.Dynamin-related protein 1 and mitochondrial fragmentation in neurodegen-erative diseases. Brain Res. Rev. 67, 103–118.

Reilly, M.M., 2007. Sorting out the inherited neuropathies. Pract. Neurol. 7, 93–105.Reilly, M.M., Murphy, S.M., Laura, M., 2011. Charcot–Marie–Tooth disease. J. Per-

ipher. Nerv. Syst. 16, 1–14.Renkawek, K., Stege, G.J., Bosman, G.J., 1999. Dementia, gliosis and expression of the

small heat shock proteins hsp27 and alpha B-crystallin in Parkinson’s disease.Neuroreport 10, 2273–2276.

Reyes-Turcu, F.E., Ventii, K.H., Wilkinson, K.D., 2009. Regulation and cellular rolesof ubiquitin-specific deubiquitinating enzymes. Annu. Rev. Biochem 78, 363–397.

Rishal, I., Fainzilber, M., 2010. Retrograde signaling in axonal regeneration. Exp.Neurol. 223, 5–10.

Roberts, R.C., Peden, A.A., Buss, F., Bright, N.A., Latouche, M., Reilly, M.M., Kendrick-Jones, J., Luzio, J.P., 2010. Mistargeting of SH3TC2 away from the recyclingendosome causes Charcot–Marie–Tooth disease type 4C. Hum. Mol. Genet. 19,1009–1018.

Robinson, F.L., Dixon, J.E., 2005. The phosphoinositide-3-phosphatase MTMR2associates with MTMR13, a membrane-associated pseudophosphatase alsomutated in type 4B Charcot–Marie–Tooth disease. J. Biol. Chem. 280, 31699–31707.

Robinson, F.L., Dixon, J.E., 2006. Myotubularin phosphatases: policing 3-phosphoi-nositides. Trends Cell Biol. 16, 403–412.

Rojas, R., van Vlijmen, T., Mardones, G.A., Prabhu, Y., Rojas, A.L., Mohammed, S.,Heck, A.J., Raposo, G., van der Sluijs, P., Bonifacino, J.S., 2008. Regulation ofretromer recruitment to endosomes by sequential action of Rab5 and Rab7. J.Cell Biol. 183, 513–526.

Rojo, M., Legros, F., Chateau, D., Lombes, A., 2002. Membrane topology and mito-chondrial targeting of mitofusins, ubiquitous mammalian homologs of thetransmembrane GTPase Fzo. J. Cell Sci. 115, 1663–1674.

Rossi, M., De Laurenzi, V., Munarriz, E., Green, D.R., Liu, Y.C., Vousden, K.H., Cesareni,G., Melino, G., 2005. The ubiquitin-protein ligase Itch regulates p73 stability.EMBO J. 24, 836–848.

Rossman, K.L., Der, C.J., Sondek, J., 2005. GEF means go: turning on RHO GTPaseswith guanine nucleotide-exchange factors. Nat. Rev. Mol. Cell Biol. 6, 167–180.

Roth, M.G., 2004. Phosphoinositides in constitutive membrane traffic. Physiol. Rev.84, 699–730.

Rubinsztein, D.C., Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., O’Kane, C.J.,Brown, S.D., 2005. Dyneins, autophagy, aggregation and neurodegeneration.Autophagy 1, 177–178.


Rudge, S.A., Anderson, D.M., Emr, S.D., 2004. Vacuole size control: regulation ofPtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, aPtdIns(3,5)P2-specific phosphatase. Mol. Biol. Cell 15, 24–36.

Rusten, T.E., Rodahl, L.M., Pattni, K., Englund, C., Samakovlis, C., Dove, S., Brech, A.,Stenmark, H., 2006. Fab1 phosphatidylinositol 3-phosphate 5-kinase controlstrafficking but not silencing of endocytosed receptors. Mol. Biol. Cell 17, 3989–4001.

Rutherford, A.C., Traer, C., Wassmer, T., Pattni, K., Bujny, M.V., Carlton, J.G., Sten-mark, H., Cullen, P.J., 2006. The mammalian phosphatidylinositol 3-phosphate5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. J. Cell Sci.119, 3944–3957.

Ryan, M.C., Shooter, E.M., Notterpek, L., 2002. Aggresome formation in neuropathymodels based on peripheral myelin protein 22 mutations. Neurobiol. Dis. 10,109–118.

Sablin, E.P., 2000. Kinesins and microtubules: their structures and motor mecha-nisms. Curr. Opin. Cell Biol. 12, 35–41.

Saifi, G.M., Szigeti, K., Wiszniewski, W., Shy, M.E., Krajewski, K., Hausmanowa-Petrusewicz, I., Kochanski, A., Reeser, S., Mancias, P., Butler, I., Lupski, J.R., 2005.SIMPLE mutations in Charcot–Marie–Tooth disease and the potential role of itsprotein product in protein degradation. Hum. Mutat. 25, 372–383.

Sakisaka, T., Takai, Y., 2005. Purification and properties of Rab3 GEP (DENN/MADD).Methods Enzymol. 403, 254–261.

Salinas, S., Bilsland, L.G., Schiavo, G., 2008. Molecular landmarks along the axonalroute: axonal transport in health and disease. Curr. Opin. Cell Biol. 20, 445–453.

Santel, A., 2006. Get the balance right: mitofusins roles in health and disease.Biochim. Biophys. Acta 1763, 490–499.

Sasaki, T., Gotow, T., Shiozaki, M., Sakaue, F., Saito, T., Julien, J.P., Uchiyama, Y.,Hisanaga, S., 2006. Aggregate formation and phosphorylation of neurofilament-L Pro22 Charcot–Marie–Tooth disease mutants. Hum. Mol. Genet. 15, 943–952.

Saxena, S., Bucci, C., Weis, J., Kruttgen, A., 2005a. The small GTPase Rab7 controls theendosomal trafficking and neuritogenic signaling of the nerve growth factorreceptor TrkA. J. Neurosci. 25, 10930–10940.

Saxena, S., Howe, C.L., Cosgaya, J.M., Steiner, P., Hirling, H., Chan, J.R., Weis, J.,Kruttgen, A., 2005b. Differential endocytic sorting of p75NTR and TrkA inresponse to NGF: a role for late endosomes in TrkA trafficking. Mol. Cell.Neurosci. 28, 571–587.

Sbrissa, D., Ikonomov, O.C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., Shisheva, A.,2007. Core protein machinery for mammalian phosphatidylinositol 3,5-bispho-sphate synthesis and turnover that regulates the progression of endosomaltransport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J. Biol.Chem. 282, 23878–23891.

Sbrissa, D., Ikonomov, O.C., Shisheva, A., 1999. PIKfyve, a mammalian ortholog ofyeast Fab1p lipid kinase, synthesizes 5-phosphoinositides – effect of insulin. J.Biol. Chem. 274, 21589–21597.

Schafer, D.A., Weed, S.A., Binns, D., Karginov, A.V., Parsons, J.T., Cooper, J.A., 2002.Dynamin2 and cortactin regulate actin assembly and filament organization.Curr. Biol. 12, 1852–1857.

Schekman, R., Orci, L., 1996. Coat proteins and vesicle budding. Science 271, 1526–1533.

Schenone, A., Nobbio, L., Monti Bragadin, M., Ursino, G., Grandis, M., 2011. Inheritedneuropathies. Curr. Treat. Options Neurol. 13, 160–179.

Scherer, S.S., Wrabetz, L., 2008. Molecular mechanisms of inherited demyelinatingneuropathies. Glia 56, 1578–1589.

Scherer, S.S., Xu, Y.T., Bannerman, P.G., Sherman, D.L., Brophy, P.J., 1995. Periaxinexpression in myelinating Schwann cells: modulation by axon–glial interac-tions and polarized localization during development. Development 121, 4265–4273.

Schiavone, F., Fracasso, C., Mostacciuolo, M.L., 1996. Novel missense mutation of theconnexin32 (GJB1) gene in X-linked dominant Charcot–Marie–Tooth neuropa-thy. Hum. Mutat. 8, 83–84.

Schlisio, S., Kenchappa, R.S., Vredeveld, L.C., George, R.E., Stewart, R., Greulich, H.,Shahriari, K., Nguyen, N.V., Pigny, P., Dahia, P.L., Pomeroy, S.L., Maris, J.M., Look,A.T., Meyerson, M., Peeper, D.S., Carter, B.D., Kaelin, W.G.J., 2008. The kinesinKIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential1p36 tumor suppressor. Genes Dev. 22, 884–893.

Schlunck, G., Damke, H., Kiosses, W.B., Rusk, N., Symons, M.H., Waterman-Storer,C.M., Schmid, S.L., Schwartz, M.A., 2004. Modulation of Rac localization andfunction by dynamin. Mol. Biol. Cell 15, 256–267.

Schmitz, G., Grandl, M., 2009. The molecular mechanisms of HDL and associatedvesicular trafficking mechanisms to mediate cellular lipid homeostasis. Arter-ioscler. Thromb. Vasc. Biol. 29, 1718–1722.

Schneider, G.B., Hamano, H., Cooper, L.F., 1998. In vivo evaluation of hsp27 as aninhibitor of actin polymerization: Hsp27 limits actin stress fiber and focaladhesion formation after heat shock. J. Cell. Physiol. 177, 575–584.

Schnorrer, F., Bohmann, K., Nusslein-Volhard, C., 2000. The molecular motor dyneinis involved in targeting swallow and bicoid RNA to the anterior pole ofDrosophila oocytes. Nat. Cell Biol. 2, 185–190.

Scholey, J.M., 2003. Intraflagellar transport. Annu. Rev. Cell Dev. Biol. 19, 423–443.Schroeder, B., Weller, S.G., Chen, J., Billadeau, D., McNiven, M.A., 2010. A Dyn2-

CIN85 complex mediates degradative traffic of the EGFR by regulation of lateendosomal budding. EMBO J. 29, 3039–3053.

Schroer, T.A., Steuer, E.R., Sheetz, M.P., 1989. Cytoplasmic dynein is a minus end-directed motor for membranous organelles. Cell 56, 937–946.

Schu, P.V., Takegawa, K., Fry, M.J., Stack, J.H., Waterfield, M.D., Emr, S.D., 1993.Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential forprotein sorting. Science 260, 88–91.




G Model


Schweitzer, J.K., Krivda, J.P., D’Souza-Schorey, C., 2009. Neurodegeneration inNiemann–Pick Type C disease and Huntington’s disease: impact of defects inmembrane trafficking. Curr. Drug Targets 10, 653–665.

Seabra, M., Brown, M., Goldstein, J., 1993. Retinal degeneration in choroideremia:deficiency of rab geranylgeranyl transferase. Science 259, 377–381.

Seabra, M.C., Mules, E.H., Hume, A.N., 2002. Rab GTPases, intracellular traffic anddisease. Trends Mol. Med. 8, 23–30.

Segawa, T., Nau, M.E., Xu, L.L., Chilukuri, R.N., Makarem, M., Zhang, W., Petrovics, G.,Sesterhenn, I.A., McLeod, D.G., Moul, J.W., Vahey, M., Srivastava, S., 2002.Androgen-induced expression of endoplasmic reticulum (ER) stress responsegenes in prostate cancer cells. Oncogene 21, 8749–8758.

Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P.,Timmerman, V., Chrast, R., Verheijen, M.H., Lemke, G., Battaloglu, E., Parman,Y., Erdem, S., Tan, E., Topaloglu, H., Hahn, A., Muller-Felber, W., Rizzuto, N.,Fabrizi, G.M., Stuhrmann, M., Rudnik-Schoneborn, S., Zuchner, S., MichaelSchroder, J., Buchheim, E., Straub, V., Klepper, J., Huehne, K., Rautenstrauss,B., Buttner, R., Nelis, E., Zerres, K., 2003a. Mutations in a gene encoding a novelSH3/TPR domain protein cause autosomal recessive Charcot–Marie–Tooth type4C neuropathy. Am. J. Hum. Genet. 73, 1106–1119.

Senderek, J., Bergmann, C., Weber, S., Ketelsen, U.P., Schorle, H., Rudnik-Schoneborn,S., Buttner, R., Buchheim, E., Zerres, K., 2003b. Mutation of the SBF2 gene,encoding a novel member of the myotubularin family, in Charcot–Marie–Toothneuropathy type 4B2/11p15. Hum. Mol. Genet. 12, 349–356.

Sever, S., Altintas, M.M., Nankoe, S.R., Moller, C.C., Ko, D., Wei, C., Henderson, J., delRe, E.C., Hsing, L., Erickson, A., Cohen, C.D., Kretzler, M., Kerjaschki, D., Rudensky,A., Nikolic, B., Reiser, J., 2007. Proteolytic processing of dynamin by cytoplasmiccathepsin L is a mechanism for proteinuric kidney disease. J. Clin. Invest. 117,2095–2104.

Sever, S., Muhlberg, A.B., Schmid, S.L., 1999. Impairment of dynamin’s GAP domainstimulates receptor-mediated endocytosis. Nature 398, 481–486.

Shajahan, A.N., Timblin, B.K., Sandoval, R., Tiruppathi, C., Malik, A.B., Minshall, R.D.,2004. Role of Src-induced dynamin-2 phosphorylation in caveolae-mediatedendocytosis in endothelial cells. J. Biol. Chem. 279, 20392–20400.

Shaw, E., McCue, L.A., Lawrence, C.E., Dordick, J.S., 2002. Identification of a novelclass in the alpha/beta hydrolase fold superfamily: the N-myc differentiation-related proteins. Proteins 47, 163–168.

Shi, P., Gal, J., Kwinter, D.M., Liu, X., Zhu, H., 2010. Mitochondrial dysfunction inamyotrophic lateral sclerosis. Biochim. Biophys. Acta 1802, 45–51.

Shidara, Y., Hollenbeck, P.J., 2010. Defects in mitochondrial axonal transport andmembrane potential without increased reactive oxygen species production in aDrosophila model of Friedreich ataxia. J. Neurosci. 30, 11369–11378.

Shim, S., Ming, G.-l., 2010. Roles of channels and receptors in the growth cone duringPNS axonal regeneration. Exp. Neurol. 223, 38–44.

Shimono, A., Okuda, T., Kondoh, H., 1999. N-myc-dependent repression of ndr1, agene identified by direct subtraction of whole mouse embryo cDNAs betweenwild type and N-myc mutant. Mech. Dev. 83, 39–52.

Shimura, H., Miura-Shimura, Y., Kosik, K.S., 2004. Binding of tau to heat shockprotein 27 leads to decreased concentration of hyperphosphorylated tau andenhanced cell survival. J. Biol. Chem. 279, 17957–17962.

Shin, J.S., Chung, K.W., Cho, S.Y., Yun, J., Hwang, S.J., Kang, S.H., Cho, E.M., Kim, S.M.,Choi, B.O., 2008a. NEFL Pro22Arg mutation in Charcot–Marie–Tooth diseasetype 1. J. Hum. Genet. 53, 936–940.

Shin, N., Ahn, N., Chang-Ileto, B., Park, J., Takei, K., Ahn, S.G., Kim, S.A., Di Paolo, G.,Chang, S., 2008b. SNX9 regulates tubular invagination of the plasma membranethrough interaction with actin cytoskeleton and dynamin 2. J. Cell Sci. 12, 1252–1263.

Shirendeb, U.P., Calkins, M., Manczak, M., Anekonda, V., Dufour, B., McBride, J.L.,Mao, P., Reddy, P.H., 2012. Mutant huntingtin’s interaction with mitochondrialprotein Drp1 impairs mitochondrial biogenesis and causes defective axonaltransport and synaptic degeneration in Huntington’s disease. Hum. Mol. Genet.21, 406–420.

Shirendeb, U., Reddy, A.P., Manczak, M., Calkins, M.J., Mao, P., Tagle, D.A., Reddy,P.H., 2011. Abnormal mitochondrial dynamics, mitochondrial loss and mutanthuntingtin oligomers in Huntington’s disease: implications for selective neu-ronal damage. Hum. Mol. Genet. 20, 1438–1455.

Shirk, A.J., Anderson, S.K., Hashemi, S.H., Chance, P.F., Bennett, C.L., 2005. SIMPLEinteracts with NEDD4 and TSG101: evidence for a role in lysosomal sorting andimplications for Charcot–Marie–Tooth disease. J. Neurosci. Res. 82, 43–50.

Shisheva, A., 2008. PIKfyve: partners, significance, debates and paradoxes. Cell Biol.Int. 591–604.

Shy, M.E., 2006. Peripheral neuropathies caused by mutations in the myelin proteinzero. J. Neurol. Sci. 242, 55–66.

Simonsen, A., Lippe, R., Christoforidis, S., Gaullier, J.M., Brech, A., Callaghan, J., Toh,B.H., Murphy, C., Zerial, M., Stenmark, H., 1998. EEA1 links PI(3)K function toRab5 regulation of endosome fusion. Nature 394, 494–498.

Simonsen, A., Tooze, S.A., 2009. Coordination of membrane events during autop-hagy by multiple class III PI3-kinase complexes. J. Cell Biol. 186, 773–782.

Skre, H., 1974. Genetic and clinical aspects of Charcot–Marie–Tooth’s disease. Clin.Genet. 6, 98–118.

Skwarek, L.C., Boulianne, G.L., 2009. Great expectations for PIP: phosphoinositidesas regulators of signaling during development and disease. Dev. Cell 16, 12–20.

Slagsvold, T., Pattni, K., Malerod, L., Stenmark, H., 2006. Endosomal and non-endosomal functions of ESCRT proteins. Trends Cell Biol. 16, 317–326.

Smirnova, E., Griparic, L., Shurland, D.L., van der Bliek, A.M., 2001. Dynamin-relatedprotein Drp1 is required for mitochondrial division in mammalian cells. Mol.Biol. Cell 12, 2245–2256.


Snider, M.D., 2003. A role for rab7 GTPase in growth factor-regulated cell nutritionand apoptosis. Mol. Cell 12, 796–797.

Snipes, G.J., Suter, U., Welcher, A.A., Shooter, E.M., 1992. Characterization of a novelperipheral nervous system myelin protein (PMP-22/SR13). J. Cell Biol. 117, 225–238.

Sollner, T.H., 2002. Vesicle tethers promoting fusion machinery assembly. Dev. Cell2, 377–378.

Sonnichsen, B., De Renzis, S., Nielsen, E., Rietdorf, J., Zerial, M., 2000. Distinctmembrane domains on endosomes in the recycling pathway visualized bymulticolor imaging of Rab4, Rab5, and Rab11. J. Cell Biol. 149, 901–914.

Soulet, F., Schmid, S.L., Damke, H., 2006. Domain requirements for an endocytosis-independent, isoform-specific function of dynamin-2. Exp. Cell Res. 312, 3539–3545.

Soulet, F., Yarar, D., Leonard, M., Schmid, S.L., 2005. SNX9 regulates dynaminassembly and is required for efficient clathrin-mediated endocytosis. Mol. Biol.Cell 16, 2058–2067.

Spinosa, M.R., Progida, C., De Luca, A., Colucci, A.M.R., Alifano, P., Bucci, C., 2008.Functional characterization of Rab7 mutant proteins associated with Charcot–Marie–Tooth type 2B disease. J. Neurosci. 28, 1640–1648.

Sprecher, E., Ishida-Yamamoto, A., Mizrahi-Koren, M., Rapaport, D., Goldsher, D.,Indelman, M., Topaz, O., Chefetz, I., Keren, H., O’brien, T.J., Bercovich, D., Shalev,S., Geiger, D., Bergman, R., Horowitz, M., Mandel, H., 2005. A mutation inSNAP29, coding for a SNARE protein involved in intracellular trafficking, causesa novel neurocutaneous syndrome characterized by cerebral dysgenesis, neu-ropathy, ichthyosis, and palmoplantar keratoderma. Am. J. Hum. Genet. 77,242–251.

Stein, M.P., Feng, Y., Cooper, K.L., Welford, A.M., Wandinger-Ness, A., 2003. HumanVPS34 and p150 are Rab7 interacting partners. Traffic 4, 754–771.

Stendel, C., Roos, A., Deconinck, T., Pereira, J., Castagner, F., Niemann, A., Kirschner, J.,Korinthenberg, R., Ketelsen, U.P., Battaloglu, E., Parman, Y., Nicholson, G.,Ouvrier, R., Seeger, J., De Jonghe, P., Weis, J., Kruttgen, A., Rudnik-Schoneborn,S., Bergmann, C., Suter, U., Zerres, K., Timmerman, V., Relvas, J.B., Senderek, J.,2007. Peripheral nerve demyelination caused by a mutant Rho GTPase guaninenucleotide exchange factor, frabin/FGD4. Am. J. Hum. Genet. 81, 158–164.

Stendel, C., Roos, A., Kleine, H., Arnaud, E., Ozcelik, M., Sidiropoulos, P.N., Zenker, J.,Schupfer, F., Lehmann, U., Sobota, R.M., Litchfield, D.W., Luscher, B., Chrast, R.,Suter, U., Senderek, J., 2010. SH3TC2, a protein mutant in Charcot–Marie–Toothneuropathy, links peripheral nerve myelination to endosomal recycling. Brain133, 2462–2474.

Stenmark, H., 2009. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. CellBiol. 10, 513–525.

Stowers, R.S., Megeath, L.J., Gorska-Andrzejak, J., Meinertzhagen, I.A., Schwarz, T.L.,2002. Axonal transport of mitochondria to synapses depends on milton, a novelDrosophila protein. Neuron 36, 1063–1077.

Street, V.A., Bennett, C.L., Goldy, J.D., Shirk, A.J., Kleopa, K.A., Tempel, B.L., Lipe, H.P.,Scherer, S.S., Bird, T.D., Chance, P.F., 2003. Mutation of a putative proteindegradation gene LITAF/SIMPLE in Charcot–Marie–Tooth disease 1C. Neurology60, 22–26.

Stromer, T., Ehrnsperger, M., Gaestel, M., Buchner, J., 2003. Analysis of the interac-tion of small heat shock proteins with unfolding proteins. J. Biol. Chem. 278,18015–18021.

Stum, M., McLaughlin, H.M., Kleinbrink, E.L., Miers, K.E., Ackerman, S.L., Seburn, K.L.,Antonellis, A., Burgess, R.W., 2011. An assessment of mechanisms underlyingperipheral axonal degeneration caused by aminoacyl-tRNA synthetase muta-tions. Mol. Cell. Neurosci. 46, 432–443.

Styers, M.L., Kowalczyk, A.P., Faundez, V., 2005. Intermediate filaments and vesicu-lar membrane traffic: the odd couple’s first dance? Traffic 6, 359–365.

Styers, M.L., Salazar, G., Love, R., Peden, A.A., Kowalczyk, A.P., Faundez, V., 2004. Theendo-lysosomal sorting machinery interacts with the intermediate filamentcytoskeleton. Mol. Biol. Cell 15, 5369–5382.

Suen, D.F., Norris, K.L., Youle, R.J., 2008. Mitochondrial dynamics and apoptosis.Genes Dev. 22, 1577–1590.

Sun, X., Fontaine, J.M., Rest, J.S., Shelden, E.A., Welsh, M.J., Benndorf, R., 2004.Interaction of human HSP22 (HspB8) with other small heat shock proteins. J.Biol. Chem. 279, 2394–2402.

Sun, Y., MacRae, T.H., 2005. The small heat shock proteins and their role in humandisease. FEBS J. 272, 2613–2627.

Suter, U., Scherer, S.S., 2003. Disease mechanisms in inherited neuropathies. Nat.Rev. Neurosci. 4, 714–726.

Szebenyi, G., Morfini, G.A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D.L., Young,M., Faber, P.W., MacDonald, M.E., McPhaul, M.J., Brady, S.T., 2003. Neuropatho-genic forms of huntingtin and androgen receptor inhibit fast axonal transport.Neuron 40, 41–52.

Szigeti, K., Lupski, J.R., 2009. Charcot–Marie–Tooth disease. Eur. J. Hum. Genet. 17,703–710.

Sztul, E., Lupashin, V., 2009. Role of vesicle tethering factors in the ER-Golgimembrane traffic. FEBS Lett. 583, 3770–3783.

Takai, Y., Sasaki, T., Shirataki, H., Nakanishi, H., 1996. Rab3A small GTP-bindingprotein in Ca(2+)-dependent exocytosis. Genes Cells 1, 615–632.

Takashima, H., Boerkoel, C.F., De Jonghe, P., Ceuterick, C., Martin, J.J., Voit, T.,Schroder, J.M., Williams, A., Brophy, P.J., Timmerman, V., Lupski, J.R., 2002.Periaxin mutations cause a broad spectrum of demyelinating neuropathies.Ann. Neurol. 51, 709–715.

Takenawa, T., Itoh, T., 2001. Phosphoinositides, key molecules for regulation of actincytoskeletal organization and membrane traffic from the plasma membrane.Biochim. Biophys. Acta 1533, 190–206.




G Model


Tanabe, K., Takei, K., 2009. Dynamic instability of microtubules requires dynamin 2and is impaired in a Charcot–Marie-Tooth mutant. J. Cell Biol. 185, 939–948.

Tanaka, K., Sugiura, Y., Ichishita, R., Mihara, K., Oka, T., 2011. KLP6: a newlyidentified kinesin that regulates the morphology and transport of mitochondriain neuronal cells. J. Cell Sci. 124, 2457–2465.

Tanaka, M., Miyoshi, J., Ishizaki, H., Togawa, A., Ohnishi, K., Endo, K., Matsubara, K.,Mizoguchi, A., Nagano, T., Sato, M., Sasaki, T., Takai, Y., 2001. Role of Rab3 GDP/GTP exchange protein in synaptic vesicle trafficking at the mouse neuromus-cular junction. Mol. Biol. Cell 12, 1421–1430.

Tanaka, Y., Kanai, Y., Okada, Y., Nonaka, S., Takeda, S., Harada, A., Hirokawa, N., 1998.Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results inabnormal perinuclear clustering of mitochondria. Cell 93, 1147–1158.

Tang, B.S., Zhao, G.H., Luo, W., Xia, K., Cai, F., Pan, Q., Zhang, R.X., Zhang, F.F., Liu, X.M.,Chen, B., Zhang, C., Shen, L., Jiang, H., Long, Z.G., Dai, H., 2005. Small heat shockprotein 22 mutated in autosomal dominant Charcot–Marie–Tooth disease type2L. Hum. Genet. 116, 222–224.

Tankisi, H., Pugdahl, K., Johnsen, B., Fuglsang-Frederiksen, A., 2007. Correlations ofnerve conduction measures in axonal and demyelinating polyneuropathies.Clin. Neurophysiol. 118, 2383–2392.

Tarabeux, J., Champagne, N., Brustein, E., Hamdan, F.F., Gauthier, J., Lapointe, M.,Maios, C., Piton, A., Spiegelman, D., Henrion, E., Millet, B., Rapoport, J.L., Delisi,L.E., Joober, R., Fathalli, F., Fombonne, E., Mottron, L., Forget-Dubois, N., Boivin,M., Michaud, J.L., Lafreniere, R.G., Drapeau, P., Krebs, M.O., Rouleau, G.A., 2010.De novo truncating mutation in Kinesin 17 associated with schizophrenia. Biol.Psychiatry 68, 649–656.

TerBush, D.R., Maurice, T., Roth, D., Novick, P., 1996. The Exocyst is a multiproteincomplex required for exocytosis in Saccharomyces cerevisiae. EMBO J. 15, 6483–6494.

Thompson, H.M., Cao, H., Chen, J., Euteneuer, U., McNiven, M.A., 2004. Dynamin 2binds gamma-tubulin and participates in centrosome cohesion. Nat. Cell Biol. 6,335–342.

Thompson, H.M., Skop, A.R., Euteneuer, U., Meyer, B.J., McNiven, M.A., 2002. Thelarge GTPase dynamin associates with the spindle midzone and is required forcytokinesis. Curr. Biol. 12, 2111–2117.

Thrower, J.S., Hoffman, L., Rechsteiner, M., Pickart, C.M., 2000. Recognition of thepolyubiquitin proteolytic signal. EMBO J. 19, 94–102.

Timmerman, V., De Jonghe, P., Ceuterick, C., De Vriendt, E., Lofgren, A., Nelis, E.,Warner, L.E., Lupski, J.R., Martin, J.J., Van Broeckhoven, C., 1999. Novel missensemutation in the early growth response 2 gene associated with Dejerine–Sottassyndrome phenotype. Neurology 52, 1827–1832.

Timmerman, V., Nelis, E., Van Hul, W., Nieuwenhuijsen, B.W., Chen, K.L., Wang, S.,Ben Othman, K., Cullen, B., Leach, R.J., Hanemann, C.O., De Jonghe, P., Raey-maekers, P., van Ommen, G.-J.B., Martin, J.-J., Muller, H.W., Vance, J.M., Fisch-beck, K.H., Van Broeckhoven, C., 1992. The peripheral myelin protein gene PMP-22 is contained within the Charcot–Marie–Tooth disease type 1A duplication.Nat. Genet. 1, 173–175.

Tooze, S.A., Schiavo, G., 2008. Liaisons dangereuses: autophagy, neuronal survivaland neurodegeneration. Curr. Opin. Neurobiol. 18, 504–515.

Torre, E., McNiven, M.A., Urrutia, R., 1994. Dynamin 1 antisense oligonucleotidetreatment prevents neurite formation in cultured hippocampal neurons. J. Biol.Chem. 269, 32411–32417.

Trajkovic, K., Dhaunchak, A.S., Goncalves, J.T., Wenzel, D., Schneider, A., Bunt, G.,Nave K.A. and Simons, M., 2006. Neuron to glia signaling triggers myelinmembrane exocytosis from endosomal storage sites. J. Cell Biol. 172, 937–948.

Trushina, E., Dyer, R.B., Badger, J.D.I.I., Ure, D., Eide, L., Tran, D.D., Vrieze, B.T.,Legendre-Guillemin, V., McPherson, P.S., Mandavilli, B.S., Van Houten, B., Zeitlin,S., McNiven, M., Aebersold, R., Hayden, M., Parisi, J.E., Seeberg, E., Dragatsis, I.,Doyle, K., Bender, A., Chacko, C., McMurray, C.T., 2004. Mutant huntingtinimpairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol.Cell. Biol. 24, 8195–8209.

Tsujita, K., Itoh, T., Ijuin, T., Yamamoto, A., Shisheva, A., Laporte, J., Takenawa, T.,2004. Myotubularin regulates the function of the late endosome through thegram domain-phosphatidylinositol 3,5-bisphosphate interaction. J. Biol. Chem.279, 13817–13824.

Tu, L.C., Yan, X., Hood, L., Lin, B., 2007. Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgenresponse program in prostate cancer cells. Mol. Cell. Proteomics 6, 575–588.

Tucker, B.A., Mearow, K.M., 2008. Peripheral sensory axon growth: from receptorbinding to cellular signaling. Can. J. Neurol. Sci. 35, 551–566.

Uchida, A., Alami, N.H., Brown, A., 2009. Tight functional coupling of kinesin-1A anddynein motors in the bidirectional transport of neurofilaments. Mol. Biol. Cell20, 4997–5006.

Ullrich, O., Reinsch, S., Urbe, S., Zerial, M., Parton, R.G., 1996. Rab11 regulatesrecycling through the pericentriolar recycling endosome. J. Cell Biol. 135,913–924.

Umikawa, M., Obaishi, H., Nakanishi, H., Satoh-Horikawa, K., Takahashi, K., Hotta, I.,Matsuura, Y., Takai, Y., 1999. Association of frabin with the actin cytoskeleton isessential for microspike formation through activation of Cdc42 small G protein.J. Biol. Chem. 274, 25197–25200.

Urrutia, R., McNiven, M.A., Albanesi, J.P., Murphy, D.B., Kachar, B., 1991. Purifiedkinesin promotes vesicle motility and induces active sliding between micro-tubules in vitro. Proc. Natl. Acad. Sci. U.S.A. 88, 6701–6705.

Vaccari, I., Dina, G., Tronchere, H., Kaufman, E., Chicanne, G., Cerri, F., Wrabetz, L.,Payrastre, B., Quattrini, A., Weisman, L.S., Meisler, M.H., Bolino, A., 2011. Geneticinteraction between MTMR2 and FIG4 phospholipid phosphatases involved inCharcot–Marie–Tooth neuropathies. PLoS Genet. 7, e1002319.


Valentijn, L.J., Bolhuis, P.A., Zorn, I., Hoogendijk, J.E., van den Bosch, N., Hensels,G.W., Stanton, V.P.J., Housman, D.E., Fischbeck, K.H., Ross, D.A., Nicholson, G.A.,Meershoek, E.J., Dauwerse, H.G., v.O., G-J.B., Baas, F., 1992. The peripheralmyelin gene PMP-22/GAS-3 is duplicated in Charcot–Marie–Tooth disease type1A. Nat. Genet. 1, 166–170.

van Belzen, N., Dinjens, W.N., Diesveld, M.P., Groen, N.A., van der Made, A.C.,Nozawa, Y., Vlietstra, R., Trapman, J., Bosman, F.T., 1997. A novel gene whichis up-regulated during colon epithelial cell differentiation and down-regulatedin colorectal neoplasms. Lab. Invest. 77, 85–92.

Varon, R., Gooding, R., Steglich, C., Marns, L., Tang, H., Angelicheva, D., Yong, K.K.,Ambrugger, P., Reinhold, A., Morar, B., Baas, F., Kwa, M., Tournev, I., Guerguel-cheva, V., Kremensky, I., Lochmuller, H., Mullner-Eidenbock, A., Merlini, L.,Neumann, L., Burger, J., Walter, M., Swoboda, K., Thomas, P.K., von Moers, A.,Risch, N., Kalaydjieva, L., 2003. Partial deficiency of the C-terminal-domainphosphatase of RNA polymerase II is associated with congenital cataracts facialdysmorphism neuropathy syndrome. Nat. Genet. 35, 185–189.

Verhoeven, K., Claeys, K.G., Zuchner, S., Schroder, J.M., Weis, J., Ceuterick, C.,Jordanova, A., Nelis, E., De Vriendt, E., Van Hul, M., Seeman, P., Mazanec, R.,Saifi, G.M., Szigeti, K., Mancias, P., Butler, I.J., Kochanski, A., Ryniewicz, B., DeBleecker, J., Van den Bergh, P., Verellen, C., Van Coster, R., Goemans, N., Auer-Grumbach, M., Robberecht, W., Milic Rasic, V., Nevo, Y., Tournev, I., Guer-gueltcheva, V., Roelens, F., Vieregge, P., Vinci, P., Moreno, M.T., Christen, H.J.,Shy, M.E., Lupski, J.R., Vance, J.M., De Jonghe, P., Timmerman, V., 2006. MFN2mutation distribution and genotype/phenotype correlation in Charcot–Marie–Tooth type 2. Brain 129, 2093–2102.

Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon,J.M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A., Van Gerwen, V.,Wagner, K., Hartung, H.P., Timmerman, V., 2003a. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot–Marie–Tooth type 2B neurop-athy. Am. J. Hum. Genet. 72, 722–727.

Verhoeven, K., De Jonghe, P., Van de Putte, T., Nelis, E., Zwijsen, A., Verpoorten, N., DeVriendt, E., Jacobs, A., Van Gerwen, V., Francis, A., Ceuterick, C., Huylebroeck, D.,Timmerman, V., 2003b. Slowed conduction and thin myelination of peripheralnerves associated with mutant rho Guanine-nucleotide exchange factor 10. Am.J. Hum. Genet. 73, 926–932.

Verma, P., Chierzi, S., Codd, A.M., Campbell, D.S., Meyer, R.L., Holt, C.E., Fawcett, J.W.,2005. Axonal protein synthesis and degradation are necessary for efficientgrowth cone regeneration. J. Neurosci. 25, 331–342.

Verstreken, P., Ly, C.V., Venken, K.J., Koh, T.W., Zhou, Y., Bellen, H.J., 2005. Synapticmitochondria are critical for mobilization of reserve pool vesicles at Drosophilaneuromuscular junctions. Neuron 47, 365–378.

Vitelli, R., Santillo, M., Lattero, D., Chiariello, M., Bifulco, M., Bruni, C., Bucci, C., 1997.Role of the small GTPase Rab7 in the late endocytic pathway. J. Biol. Chem. 272,4391–4397.

Vleminckx, V., Van Damme, P., Goffin, K., Delye, H., Van Den, B.L., Robberecht, W.,2002. Upregulation of HSP27 in a transgenic model of ALS. J. Neuropathol. Exp.Neurol. 61, 968–974.

Vogiatzi, T., Xilouri, M., Vekrellis, K., Stefanis, L., 2008. Wild type a-synuclein isdegraded by chaperone mediated autophagy and macroautophagy in neuronalcells. J. Biol. Chem. 283, 23542–23556.

Vos, M.J., Hageman, J., Carra, S., Kampinga, H.H., 2008. Structural and functionaldiversities between members of the human HSPB, HSPH, HSPA, and DNAJchaperone families. Biochemistry 47, 7001–7011.

Voss, O.H., Batra, S., Kolattukudy, S.J., Gonzalez-Mejia, M.E., Smith, J.B., Doseff, A.I.,2007. Binding of caspase-3 prodomain to heat shock protein 27 regulatesmonocyte apoptosis by inhibiting caspase-3 proteolytic activation. J. Biol.Chem. 282, 25088–25099.

Wagner, K.M., Ruegg, M., Niemann, A., Suter, U., 2009. Targeting and function of themitochondrial fission factor GDAP1 are dependent on its tail-anchor. PLoS ONE4, e5160.

Wagner, O.I., Ascano, J., Tokito, M., Leterrier, J.F., Janmey, P.A., Holzbaur, E.L., 2004.The interaction of neurofilaments with the microtubule motor cytoplasmicdynein. Mol. Biol. Cell 15, 5092–5100.

Wang, L., Brown, A., 2010. A hereditary spastic paraplegia mutation in kinesin-1A/KIF5A disrupts neurofilament transport. Mol. Neurodegener. 5, 52.

Wang, T., Hong, W., 2002. Interorganellar regulation of lysosome positioning by theGolgi apparatus through Rab34 interaction with Rab-interacting lysosomalprotein. Mol. Biol. Cell 13, 4317–4332.

Warner, L.E., Mancias, P., Butler, I.J., McDonald, C.M., Keppen, L., Koob, K.G., Lupski,J.R., 1998. Mutations in the early growth response 2 (EGR2) gene are associatedwith hereditary myelinopathies. Nat. Genet. 18, 382–384.

Warnock, D.E., Baba, T., Schmid, S.L., 1997. Ubiquitously expressed dynamin-II has ahigher intrinsic GTPase activity and a greater propensity for self-assembly thanneuronal dynamin-I. Mol. Biol. Cell 8, 2553–2562.

Wassmer, T., Attar, N., Harterink, M., van Weering, J.R., Traer, C.J., Oakley, J., Goud,B., Stephens, D.J., Verkade, P., Korswagen, H.C., Cullen, P.J., 2009. The retromercoat complex coordinates endosomal sorting and dynein-mediated transport,with carrier recognition by the trans-Golgi network. Dev. Cell 17, 110–122.

Watt, S.A., Kular, G., Fleming, I.N., Downes, C.P., Lucocq, J.M., 2002. Subcellularlocalization of phosphatidylinositol 4,5-bisphosphate using the pleckstrin ho-mology domain of phospholipase C delta1. Biochem. J. 363, 657–666.

Weigert, R., Silletta, M.G., Spano, S., Turacchio, G., Cericola, C., Colanzi, A., Senatore,S., Mancini, R., Polishchuk, E.V., Salmona, M., Facchiano, F., Burger, K.N., Mir-onov, A., Luini, A., Corda, D., 1999. CtBP/BARS induces fission of Golgi mem-branes by acylating lysophosphatidic acid. Nature 402, 429–433.




G Model


Weller, S.G., Capitani, M., Cao, H., Micaroni, M., Luini, A., Sallese, M., McNiven, M.A.,2010. Src kinase regulates the integrity and function of the Golgi apparatus viaactivation of dynamin 2. Proc. Natl. Acad. Sci. U.S.A. 107, 5863–5868.

Wen, P.J., Osborne, S.L., Meunier, F.A., 2011. Dynamic control of neuroexocytosis byphosphoinositides in health and disease. Prog. Lipid Res. 50, 52–61.

Westermann, B., 2010. Mitochondrial fusion and fission in cell life and death. 2. Nat.Rev. Mol. Cell Biol. 11, 872–884.

Whittard, J.D., Craig, S.E., Mould, A.P., Koch, A., Pertz, O., Engel, J., Humphries, M.J.,2002. E-cadherin is a ligand for integrin alpha2beta1. Matrix Biol. 21, 525–532.

Wickner, W., 2010. Membrane fusion: five lipids, four SNAREs, three chaperones,two nucleotides, and a Rab, all dancing in a ring on yeast vacuoles. Annu. Rev.Cell Dev. Biol. 26, 115–136.

Williams, K.L., Rahimtula, M., Mearow, K.M., 2005. Hsp27 and axonal growth inadult sensory neurons in vitro. BMC Neurosci. 6, 24.

Wilson, J.E., 2003. Isozymes of mammalian hexokinase: structure, subcellularlocalization and metabolic function. J. Exp. Biol. 206, 2049–2057.

Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R.,Reed, J.A., Dierick, I., Verpoorten, N., Warner, T.T., Proukakis, C., Van den Bergh,P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V.,Crosby, A.H., Wagner, K., 2004. Heterozygous missense mutations in BSCL2 areassociated with distal hereditary motor neuropathy and Silver syndrome. Nat.Genet. 36, 271–276.

Winterstein, C., Trotter, J., Kramer-Albers, E.M., 2008. Distinct endocytic recycling ofmyelin proteins promotes oligodendroglial membrane remodeling. J. Cell Sci.121, 834–842.

Wong, E., Cuervo, A.M., 2010. Autophagy gone awry in neurodegenerative diseases.Nat. Neurosci. 13, 806–811.

Worman, H.J., Ostlund, C., Wang, Y., 2010. Diseases of the nuclear envelope. ColdSpring Harb. Perspect. Biol. 2, a000760.

Wu, Z., Ghosh-Roy, A., Yanik, M.F., Zhang, J.Z., Jin, Y., Chisholm, A.D., 2007. Cae-norhabditis elegans neuronal regeneration is influenced by life stage, ephrinsignaling, and synaptic branching. Proc. Natl. Acad. Sci. U.S.A. 104, 15132–15137.

Xia, C.H., Roberts, E.A., Her, L.S., Liu, X., Williams, D.S., Cleveland, D.W., Goldstein,L.S., 2003. Abnormal neurofilament transport caused by targeted disruption ofneuronal kinesin heavy chain KIF5A. J. Cell Biol. 161, 55–66.

Yamamoto, A., Simonsen, A., 2011. The elimination of accumulated and aggregatedproteins: a role for aggrephagy in neurodegeneration. Neurobiol. Dis. 43, 17–28.

Yamauchi, J., Torii, T., Kusakawa, S., Sanbe, A., Nakamura, K., Takashima, S., Hama-saki, H., Kawaguchi, S., Miyamoto, Y., Tanoue, A., 2010. The mood stabilizervalproic acid improves defective neurite formation caused by Charcot–Marie–Tooth disease-associated mutant Rab7 through the JNK signaling pathway. J.Neurosci. Res. 88, 3189–3197.

Yasuda, T., Ohtsuka, T., Inoue, E., Yokoyama, S., Sakisaka, T., Kodama, A., Takaishi, K.,Takai, Y., 2000. Importance of spatial activation of Cdc42 and rac small G proteinsby frabin for microspike formation in MDCK cells. Genes Cells 5, 583–591.

Yazawa, I., Giasson, B.I., Sasaki, R., Zhang, B., Joyce, S., Uryu, K., Trojanowski, J.Q., Lee,V.M., 2005. Mouse model of multiple system atrophy a-synuclein expression inoligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847–859.

Yoo, J., Jeong, M.J., Cho, H.J., Oh, E.S., Han, M.Y., 2005. Dynamin II interacts withsyndecan-4, a regulator of focal adhesion and stress-fiber formation. Biochem.Biophys. Res. Commun. 328, 424–431.

Yoshihara, T., Kanda, F., Yamamoto, M., Ishihara, H., Misu, K., Hattori, N., Chihara, K.,2001. A novel missense mutation in the early growth response 2 gene


associated with late-onset Charcot–Marie–Tooth disease type 1. J. Neurol.Sci. 184, 149–153.

Yoshimura, S., Gerondopoulos, A., Linford, A., Rigden, D.J., Barr, F.A., 2010. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. J.Cell Biol. 191, 367–381.

Yu, W.H., Cuervo, A.M., Kumar, A., Peterhoff, C.M., Schmidt, S.D., Lee, J.H., Mohan,P.S., Mercken, M., Farmery, M.R., Tjernberg, L.O., Jiang, Y., Duff, K., Uchiyama, Y.,Naslund, J., Mathews, P.M., Cataldo, A.M., Nixon, R.A., 2005. Macroautophagy—anovel Beta-amyloid peptide-generating pathway activated in Alzheimer’s dis-ease. J. Cell Biol. 171, 87–98.

Yue, Z., Wang, Q.J., Komatsu, M., 2008. Neuronal autophagy: going the distance tothe axon. Autophagy 4, 94–96.

Yum, S.W., Zhang, J., Mo, K., Li, J., Scherer, S.S., 2009. A novel recessive NEFL mutationcauses a severe, early-onset axonal neuropathy. Ann. Neurol. 66, 759–770.

Zhai, J., Lin, H., Julien, J.P., Schlaepfer, W.W., 2007. Disruption of neurofilamentnetwork with aggregation of light neurofilament protein: a common pathwayleading to motor neuron degeneration due to Charcot–Marie–Tooth disease-linked mutations in NFL and HSPB1. Hum. Mol. Genet. 16, 3103–3116.

Zhang, X., Chow, C.Y., Sahenk, Z., Shy, M.E., Meisler, M.H., Li, J., 2008a. Mutation ofFIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain131, 1990–2001.

Zhang, X., Orlando, K., He, B., Xi, F., Zhang, J., Zajac, A., Guo, W., 2008b. Membraneassociation and functional regulation of Sec3 by phospholipids and Cdc42. J. CellBiol. 180, 145–158.

Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H.W., Terada,S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., Hirokawa, N., 2001.Charcot–Marie–Tooth disease type 2a caused by mutation in a microtubulemotor kif1bb. Cell 105, 587–597.

Zheng, J., Cahill, S.M., Lemmon, M.A., Fushman, D., Schlessinger, J., Cowburn, D.,1996. Identification of the binding site for acidic phospholipids on the pHdomain of dynamin: implications for stimulation of GTPase activity. J. Mol. Biol.255, 14–21.

Zink, S., Wenzel, D., Wurm, C.A., Schmitt, H.D., 2009. A link between ER tetheringand COP-I vesicle uncoating. Dev. Cell 17, 403–416.

Zinsmaier, K.E., Babic, M., Russo, G.J., 2009. Mitochondrial transport dynamics inaxons and dendrites. Results Probl. Cell Differ. 48, 107–139.

Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K.G., Guergueltcheva, V., Chernin-kova, S., Hamilton, S.R., Van Stavern, G., Krajewski, K.M., Stajich, J., Tournev, I.,Verhoeven, K., Langerhorst, C.T., de Visser, M., Baas, F., Bird, T., Timmerman, V.,Shy, M., Vance, J.M., 2006. Axonal neuropathy with optic atrophy is caused bymutations in mitofusin 2. Ann. Neurol. 59, 276–281.

Zuchner, S., Mersiyanova, I.V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali,E.L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O.,Jonghe, P.D., Takahashi, Y., Tsuji, S., Pericak-Vance, M.A., Quattrone, A., Batta-loglu, E., Polyakov, A.V., Timmerman, V., Schroder, J.M., Vance, J.M., 2004.Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A. Nat. Genet. 36, 449–451.

Zuchner, S., Noureddine, M., Kennerson, M., Verhoeven, K., Claeys, K., De Jonghe, P.,Merory, J., Oliveira, S.A., Speer, M.C., Stenger, J.E., Walizada, G., Zhu, D., Pericak-Vance, M.A., Nicholson, G., Timmerman, V., Vance, J.M., 2005. Mutations in thepleckstrin homology domain of dynamin 2 cause dominant intermediateCharcot–Marie-Tooth disease. Nat. Genet. 37, 289–294.

Zuchner, S., Vance, J.M., 2006. Molecular genetics of autosomal-dominant axonalCharcot–Marie–Tooth disease. Neuromol. Med. 8, 63–74.



Charcot–Marie–Tooth disease and intracellular traffic

Documents

Transcript of Charcot–Marie–Tooth disease and intracellular traffic