Charcot-Marie-Tooth disease: Emerging mechanisms and therapies

Charcot-Marie-Tooth disease: Emerging mechanisms and therapies

The International Journal of Biochemistry & Cell Biology 44 (2012) 1299–1304 Contents lists available at SciVerse ScienceDirect The International Jo...

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The International Journal of Biochemistry & Cell Biology 44 (2012) 1299–1304

Contents lists available at SciVerse ScienceDirect

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Charcot-Marie-Tooth disease: Emerging mechanisms and therapies Constantin d’Ydewalle a,b , Veronick Benoy a,b , Ludo Van Den Bosch a,b,∗ a b

Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Neurobiology & Leuven Research Institute for Neurodegenerative Diseases (LIND), University of Leuven, Leuven, Belgium

a r t i c l e

i n f o

Article history: Received 21 January 2012 Received in revised form 20 April 2012 Accepted 24 April 2012 Available online 30 April 2012 Keywords: Charcot-Marie-Tooth disease (CMT) Axonal transport Histone deacetylase 6 (HDAC6)

a b s t r a c t Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. The disease is characterized by a progressive muscle weakness and atrophy, sensory loss, foot (and hand) deformities and steppage gait. While many of the genes associated with axonal CMT have been identified, to date it is unknown which mechanism(s) causes the disease. However, genetic findings indicate that the underlying mechanisms mainly converge to the axonal cytoskeleton. In this review, we will summarize the evidence for this pathogenic convergence. Furthermore, recent work with new transgenic mouse models has led to the identification of histone deacetylase 6 as a potential therapeutic target for inherited peripheral neuropathies. This enzyme deacetylates microtubules and plays a crucial role in the regulation of axonal transport. These findings offer new perspectives for a potential therapy to treat axonal CharcotMarie-Tooth disease and other neurodegenerative disorders characterized by axonal transport defects. © 2012 Elsevier Ltd. All rights reserved.

Key facts: - CMT is the most common inherited disorder of the peripheral nervous system. - The mechanisms causing axonopathies converge to cytoskeletal and transport defects. - HDAC6 is an attractive therapeutic target for inherited axonopathies. 1. Introduction Charcot-Marie-Tooth disease (CMT) – also known as hereditary motor and sensory neuropathy (HMSN) – is the most common form of inherited peripheral neuropathies with an estimated prevalence of 1 in 2500 (Züchner and Vance, 2006; Barisic et al., 2008). Typically, CMT is characterized by clinical and genetic heterogeneity. However, most patients show slowly progressive distal and symmetrical muscle weakness and atrophy that affects the intrinsic foot and peroneal muscles in combination with sensory problems (Züchner and Vance, 2006; Barisic et al., 2008). Later in the disease, muscles of hands and forearms become affected. Common features are foot deformities such as hammertoes and pes cavus. These symptoms often cause steppage gait (Züchner and Vance,

∗ Corresponding author at: Laboratory of Neurobiology, Campus Gasthuisberg, O&N4, Herestraat 49 PB 912, B-3000 Leuven, Belgium. Tel.: +32 16 33 06 81; fax: +32 16 33 07 70. E-mail address: [email protected] (L. Van Den Bosch). 1357-2725/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.

2006; Barisic et al., 2008). Depending on the severity and the penetrance of the disease some patients become wheelchair-bound in late disease stages. Based on electrophysiological findings CMT patients are categorized into different types of CMT. Type 1 CMT patients (CMT1) demonstrate severely reduced motor nerve conduction velocities (mNCVs < 38 m s−1 ) that correspond to demyelination (Reilly and Shy, 2009). Type 2 CMT patients (CMT2) show normal mNCVs (>38 m s−1 ) but reduced amplitudes of the compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) due to axonal loss (Reilly and Shy, 2009). Intermediate forms of CMT (mNCVs between 25 and 45 m s−1 ) show signs of both demyelination and axonal loss (Reilly and Shy, 2009). If the disease exclusively affects motor neurons and their axons, the disease is referred to as distal hereditary motor neuropathy (distal HMN) (Reilly and Shy, 2009). Overall, approximately 80% of patients are classified as CMT1, while the remaining 20% are categorized as CMT2. The pattern of inheritance can be either autosomal dominant, autosomal recessive or X-linked (Züchner and Vance, 2006; Barisic et al., 2008). In 90% of the cases the disease is inherited in an autosomal dominant fashion. To date, more than 40 causative genes have been associated with CMT ( Moreover, some genes are linked to various subtypes of CMT. Mutations in the gene encoding neurofilament light-chain (NEFL) which is exclusively expressed in neurons can cause dominant CMT1, dominant intermediate CMT, and dominant or recessive CMT2. Conversely, the gene encoding myelin protein zero (MPZ) which is exclusively


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Table 1 Overview of CMT2, intermediate CMT and distal HMN genes. Gene






Neurofilament light-chain Mitofusin-2 Ganglioside-induced differentiation associated protein-1

8p21 1p36.22 8q21.11


Ras-related GTP binding protein-7 Dynein cytoplasmic-1 heavy-chain-1 Dynactin-1 Dynamin-2

3q21.3 14q32 2p13 19p13.2


Transient receptor potential cation channel vanilloid-4 Small 27-kDa heat-shock protein B1

12q24.1 7q11.23


Small 27-kDa heat-shock protein B3 Small 22-kDa heat-shock protein B8

5q11.2 12q24.23


Myelin protein zero



Lamin A/C Alanyl tRNA synthetase Glycyl tRNA synthetase

1q22 16q22 7p14


Lysyl tRNA synthetase Tyrosyl tRNA synthetase Immunoglobulin mu binding protein-2 Mediator-25 Berardinelli-Seip congenital lipodystrophy-2

16q23.1 1p35.1 11q13.3 19q13.3 11q13

D or R D or R D or R R D D D D R D D or R D or R D D D D D R D D D R D R R D

CMT2 CMT2 CMT2 Intermediate CMT CMT2 CMT2 Distal HMN CMT2 CMT2 CMT2 CMT2 Distal HMN Distal HMN CMT2 Distal HMN CMT2 Intermediate CMT CMT2 CMT2 CMT2 Distal HMN Intermediate CMT Intermediate CMT Distal HMN CMT2 Distal HMN

Gene name, protein name, chromosomal location, mode of inheritance and subtype of CMT are shown. D: dominant; R: recessive. a Genes that are also associated with demyelinating (type 1) CMT.

present in myelinating Schwann cells has been associated with both demyelinating and axonal CMT. These findings thus illustrate the genetic heterogeneity of the disease that can impede a correct diagnosis (Table 1). Nonetheless, most genes associated with CMT2 and distal HMN appear to converge functionally to the axonal cytoskeleton. In this review, we will focus on these two types of inherited peripheral neuropathies. Based on genetic findings, we will illustrate emerging potential mechanisms underlying these disorders. Finally, we will summarize current therapeutic strategies and indicate a promising target for both neuropathies. 2. Emerging pathogenic mechanisms Despite the genetic and clinical heterogeneity, genetic and functional studies indicate that a number of genes associated with axonal CMT and/or distal HMN show some common features in relation to their potential pathogenic mechanism (Fig. 1). Although the primary causes might be different, the diseasecausing mechanisms appear to predominantly converge to the cytoskeleton of peripheral axons and axonal transport (Fig. 1). These axons extend up to one meter from the neuronal soma to their target site making them vulnerable to cytoskeletal alterations. Moreover, the highly polarized neurons are particularly sensitive to defects in axonal transport that is largely mediated by microtubules. Defects in axonal transport have been frequently observed in neurodegenerative disorders (reviewed by de Vos et al., 2008). 2.1. CMT2 and distal HMN are cytoskeletal diseases Mutations in NEFL have been associated with CMT. NEFL is one of the three members of the neurofilament family and is expressed exclusively in neurons. Neurofilaments are the most prominent elements in the axonal cytoskeleton. Mutations in NEFL cause disruption of the neurofilament network and aggregation (Zhai et al., 2007). Conditional mutant NEFL-expressing mice phenocopy some

of the classical symptoms of CMT2 (Dequen et al., 2010). Genetic down-regulation of the mutant NEFL expression results in a partial reversal of the phenotype (Dequen et al., 2010). The most common form of CMT2 is caused by dominant mutations in the gene encoding Mitofusin-2 (MFN2). This protein is located in the outer membrane of mitochondria. MFN2 interacts with the Miro/Milton complex that serves as an adaptor to dock mitochondria to motor proteins (Guo et al., 2005; Misko et al., 2010). CMT-associated mutations in MFN2 lead to severe axonal transport defects (Baloh et al., 2007). CMT2associated mutant MFN2 also causes axonopathy in mice when over-expressed in neurons (Detmer et al., 2008; Cartoni et al., 2010). Mutations in another mitochondrial protein, gangliosideinduced differentiation-associated protein-1 (GDAP1), are also linked to axonal CMT. GDAP1 plays a role in mitochondrial fusion and fission and appears to cause mitochondrial fragmentation when mutated (Niemann et al., 2005, 2009). Although experimental data are lacking, it is tempting to speculate that mutant GDAP1 might be connected to the microtubular network in peripheral axons. This could eventually lead to mitochondrial transport defects, as is the case for mutant MFN2. In axons, small vesicles are also transported along microtubules. Mutations in RAB7 encoding Ras-associated GTP-binding protein-7 have been linked to CMT2. This small GTPase controls the vesicular transport to late endosomes and lysosomes in the endocytic pathway (Saxena, 2005). Although the consequences are still unclear, it has been shown that disease-associated mutant RAB7 has impaired GTPase activity and reduced nucleotide dissociation rates (McCray et al., 2010). RAB7 has been shown to mediate the microtubule-based transport of early melanosomes (vesicles containing melanine), suggesting a direct link between RAB7 and cytoskeletal structures. Indeed, RAB7 (and RAB5) controls endocytic sorting by axonal retrograde transport (Deinhardt et al., 2006). Finally, the RAB7-interacting lysosomal protein (RILP) controls lysosomal transport by inducing the recruitment of dynein-dynactin motor, further supporting our hypothesis (Jordens et al., 2001).

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Fig. 1. The pathogenic mechanisms underlying CMT2 and distal HMN converge to the axonal cytoskeleton. (A) Proteins associated with CMT2 and distal HMN are shown in the axon or surrounding myelin sheath. The mechanism underlying the CMT2 and distal HMN phenotype converge to the axonal cytoskeleton and axonal transport. DCTN1: dynactin-1; DYNC1H1: dynein cytoplasmic-1 heavy-chain-1; GDAP1: ganglioside-induced differentiation-associated protein-1; HSPB1, 3 or 8: small heat-shock protein B1, 3 or 8; MFN2: Mitofusin-2; MPZ: myelin protein zero; NEFL: neurofilament light-chain; RAB7: Ras-related GTP binding protein-7; TRPV4: transient receptor potential cation channel vanilloid-4. E: endosome; L: lysosome; IM: inner membrane; OM: outer membrane. (B) Other proteins associated with CMT2 and distal HMN appear to localize in the nucleus or in the neuronal soma. AA: amino acid; ARS: aminoacyl tRNA synthetases; BSCL2: Berardinelli-Seip congenital lipodystrophy-2; IGHMBP2: immunoglobulin mu binding protein-2; LMNA: lamin A/C; MED25: mediator-25. MTOC: microtubule organizing center; tRNA: transfer ribonucleic acid; TRPV4: transient receptor potential cation channel of the vanilloid-type member 4.

Recently, mutations in the heavy-chain of the dynein motor protein (encoded by DYNC1H1) have been associated with CMT2 (Weedon et al., 2011). Furthermore, mutations in Dynactin-1 (encoded by DCTN1) cause distal HMN (Puls et al., 2003). Dynactin1 is part of a multi-subunit complex that binds to the motor protein Dynein. These proteins act together and are critical for microtubule-mediated fast axonal transport (de Vos et al., 2008). Moreover, a binding assay demonstrated decreased binding of mutant Dynactin-1 to microtubules that might lead to axonal transport defects (Puls et al., 2003). The identification of mutations in genes encoding for motor proteins further emphasizes a key role of axonal transport defects in the pathogenesis of CMT2 and distal HMN. Mutations in DNM2 encoding Dynamin-2 cause CMT2 and intermediate CMT. Dynamin-2 plays a role in endocytosis, as it helps in changing the cell membrane and the underlying cytoskeletal structures to form vesicles (Züchner et al., 2005). Dynamin-2 also interacts with microtubules and the microtubule-organizing center or centrosome (Tanabe and Takei, 2009). Disease-causing mutations in DNM2 cause the prominent decoration of microtubules with DNM2 and alter microtubule dynamics, a process necessary for correct axonal transport (Tanabe and Takei, 2009). Transient receptor potential cation channel of the vanilloid-type member 4 (TRPV4) encodes for a Ca2+ permeable non-selective channel that plays a role in the regulation of systemic osmotic pressure. Recently, several mutations in TRPV4 have been identified as a cause of CMT2 and related neurodegenerative disorders. In vitro studies suggest that increased Ca2+ influx and subsequent Ca2+ overload might be the cause of the neurotoxic effects of mutant TRPV4 (Fecto et al., 2011). This excitotoxic effect might be deleterious to axonal transport, as changes in Ca2+ concentrations have been shown to influence axonal transport (de Vos et al., 2008). Likewise, the pathogenesis underlying mutant TRPV4-induced CMT2 might also converge to the axonal cytoskeleton. This hypothesis is supported by the location of the disease-causing mutations in the ankyrin-binding domains of TRPV4. Ankyrins are adaptor proteins that mediate the attachment of integral membrane proteins to the underlying cytoskeletal structures. Moreover, TRPV4 contains a C-terminal calmodulin-binding domain and regulates microtubule and actin dynamics (Cuajungco et al., 2006; Goswami et al., 2010).

These results emphasize the potential convergence of the underlying mechanism to the axonal cytoskeleton. Mutations in three (out of ten) genes encoding small heat-shock proteins (HSPBs) have been identified as a cause of either CMT2 or distal HMN. The association of mutations in molecular chaperones HSPB1, HSPB3 and HSPB8 with peripheral neuropathies emphasizes the key role of these small heat-shock proteins in neuronal integrity and function (Evgrafov et al., 2004; Irobi et al., 2004; Kolb et al., 2010). HSPBs have been implicated in the regulation of the assembly of cytoskeletal structures such as actin and intermediate filaments. Recently, it was found that mutant HSPB1 shows increased binding affinity to tubulin, the major component of microtubules (Almeida-Souza et al., 2010, 2011). Moreover, microtubules show an increased stability to cold- and nocodazole-induced depolymerization in the presence of mutant HSPB1 (Almeida-Souza et al., 2011). These data indicate that HSPBs interact and influence several components of the cytoskeletal architecture. Using transgenic mouse models for mutant HSPB1induced CMT2 and distal HMN, we observed that mutant HSPB1 affects axonal transport of mitochondria (d’Ydewalle et al., 2011). These defects are associated with a reduction in acetylated tubulin abundance in peripheral nerves of mutant HSPB1-expressing mice (d’Ydewalle et al., 2011). Together, these data strongly indicate that mutant HSPBs might disturb cytoskeletal structures leading to defects in axonal transport. Surprisingly, mutations in myelin protein zero encoded by MPZ, expressed in myelinating Schwann cells only, can give rise to axonal CMT (reviewed by Suter and Scherer, 2003). These findings indicate that the structural interaction between the myelin sheath and the axon is crucial for axonal integrity. Finally, Lamin A/C (LMNA) mutations are also a recessive cause of CMT2 (reviewed by Suter and Scherer, 2003). The lamins constitute a two-dimensional matrix next to the inner nuclear membrane. It is to date unknown how nuclear proteins cause axonal neuropathies. Recently however, extranuclear lamin B2 has been identified as a locally translated protein in axons that interacts with mitochondria (Yoon et al., 2012). Inhibition of axonal lamin B2 translation causes axonal degeneration (Yoon et al., 2012). Furthermore, lamin B2deficient axons exhibit axonal transport defects (Yoon et al., 2012). Intriguingly, mutations in lamins have been associated with


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Fig. 2. Mutant HSPB1-expressing mice display hind paw deformities as seen in CMT patients. S135F- and P182L-HSPB1-expressing mice (lower panels) demonstrate hind paw deformities that resemble the pes cavus and hammertoes frequently observed in CMT and distal HMN patients. In contrast, non-transgenic (NonTG) and wild type (WT-)HSPB1-expressing mice (upper panels) show normal hind paw (stretched) morphology.

other severe diseases including dystrophies, cardiomyopathies, and progeria. 2.2. Other disease-associated genes in CMT2 and distal HMN It is tempting to hypothesize a convergence of disease mechanisms to one final common pathway. However, there are still other mutated genes associated with CMT2 and distal HMN of which the gene products do not seem to be linked to the axonal cytoskeleton. The aminoacyl-tRNA synthetase family of enzymes belongs to the oldest enzymes in mammals. These evolutionary highly conserved enzymes catalyze in an ATP-dependent manner the aminoacylation of tRNA leading to the ligation of amino acids to their cognate tRNAs. Of the 36 aminoacyl-tRNA synthetases (including mitochondrial specific tRNA-synthetases), mutations in at least four of them have been associated with axonal forms of CMT (reviewed by Antonellis and Green, 2008). While some studies suggest a loss of enzymatic function in mutants, others hypothesize that mutant aminoacyl-tRNA synthetases exert unknown new toxic functions that cause the disease (Jordanova et al., 2006; Antonellis et al., 2006). This gain-of-function theory is further supported by the observation that the phenotype of mutant GARS mice cannot be corrected by over-expression of wild-type GARS (Motley et al., 2011). Recessive CMT2-causing mutations have been identified in Mediator-25 (encoded by MED25) (Leal et al., 2009). MED25 is part of a multi-subunit complex that interacts with a wide variety of

transcription factors and regulates chromatin remodeling through histone acetyltransferase. Finally, mutations in Berardinelli-Seip congenital lipodystrophy or Seipin (BSCL2) have been associated with distal HMN (Windpassinger et al., 2004). Little is known about the possible pathogenic mechanisms underlying these axonal neuropathies.

3. Therapy 3.1. Current treatment strategies for axonal CMT and distal HMN Currently, the treatment of CMT patients is only supportive as there are no drugs available that have a proven effect on halting/slowing disease symptoms. The therapy mainly consists of rehabilitation, orthics, symptomatic treatment of pain and surgical corrections of foot and hand deformities (Reilly and Shy, 2009; Shy, 2006). Several therapeutic approaches using progesterone and ascorbic acid are being tested in the context of demyelinating CMT in humans. Progesterone promotes myelination in the peripheral nervous system and stimulates PMP22 and MPZ expression (Désarnaud et al., 1998). Furthermore, a progesterone antagonist has shown to be beneficial in a rat model of demyelinating CMT (Sereda et al., 2003). Ascorbic acid is well known for its effects on the formation of the collagen- and laminin-containing extracellular matrix and therefore seems to promote myelination

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by Schwann cells (Eldridge et al., 1987). Currently, clinical trials are being conducted using ascorbic acid as therapeutic strategy for demyelinating CMT (Pareyson et al., 2011). 3.2. A new potential drug target for CMT2 and distal HMN We recently characterized two mutant HSPB1-expressing mice that accurately phenocopy human CMT2 and distal HMN (d’Ydewalle et al., 2011). Both mutant HSPB1-expressing mice display progressive motor disturbances due to muscle weakness and atrophy. Mutant HSPB1 also causes steppage gait and hind paw deformities resembling what is observed in individuals affected with CMT (Fig. 2) (d’Ydewalle et al., 2011). Nerve conduction studies indicate that both mutant HSPB1-expressing mice display motor axonopathy. In contrast and dependent on the mutation expressed, mutant HSPB1-expressing mice show sensory loss as demonstrated both behaviorally and electrophysiologically. Mutant HSPB1 causes mitochondrial transport defects that are associated with a reduction in acetylated tubulin levels in peripheral nerves isolated from symptomatic animals (d’Ydewalle et al., 2011). Treatment with HDAC6 inhibitors results in an increase in acetylated tubulin abundance in peripheral nerve of symptomatic mutant HSPB1expressing mice (d’Ydewalle et al., 2011). This increase restores axonal transport defects and reverses some of the key symptoms in mice including motor performance and amplitudes of motor and sensory action potentials (d’Ydewalle et al., 2011). These findings indicate that reinnervation occurs after HDAC6 inhibition. Together, these results suggest that HDAC6 inhibitors could be used as a therapeutic strategy for mutant HSPB1-induced CMT2 and distal HMN. As most genes associated with CMT2 and distal HMN appear to be linked to cytoskeletal structures and in particular to microtubules, it would be interesting to investigate whether the axonal cytoskeleton is disrupted in the presence of disease-associated proteins. Likewise, it would be informative to assess the effect of CMT2and distal HMN-linked proteins on axonal transport. HDAC6 has been shown to regulate axonal transport and HDAC6 inhibitors increase axonal transport both at baseline conditions and in diseased stages (Chen et al., 2010). 4. Conclusions HDAC6 thus appears to be an attractive target to treat axonal neuropathies (Rivieccio et al., 2009). However, while several potential therapies have been shown to be beneficial in animal models for neurodegenerative disorders, most of them only demonstrate modest efficiency in humans. Investigation of the toxicity profile, as well as other pharmacokinetic and – dynamic parameters of candidate drugs will be needed before it can be translated into human therapy. As axonal transport defects are commonly observed in other neurodegenerative disorders, HDAC6 might also offer therapeutic perspectives for motor neuron disorders such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) as well as other neurodegenerative diseases (de Vos et al., 2008). Future research using HDAC6 inhibitors in other animal models of neurodegeneration will provide information about the efficiency and efficacy of this class of drugs as a potential therapeutic strategy in humans. Acknowledgements Research of the authors is supported by grants from the Fund for Scientific Research Flanders (FWO), the University of Leuven, the Belgian government (Interuniversity Attraction Poles, program


P6/43 of the Belgian Federal Science Policy Office), the Association Belge contre les Maladies neuro-Musculaires (ABMM), the Association Franc¸aise contre les Myopathies (AFM), the Frick Foundation for Amyotrophic Lateral Sclerosis Research, the Muscular Dystrophy Association (MDA), the European Community’s Health Seventh Framework Program (FP7/2007-2013 under grant agreement 259867) and the Latran Foundation. C.d.Y. and V.B. are supported by the Agency for Innovation by Science and Technology in Flanders (IWT-Vlaanderen).

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