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HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1–induced Charcot-Marie-Tooth disease

Nature Medicine volume 17, pages 968–974 (2011)Cite this article

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Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1–induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.

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Figure 1: Neuronal expression of human mutant HSPB1 in mice leads to progressive motor defects and decreased muscle strength.
Figure 2: Mice expressing mutant HSPB1 show steppage gait and clawed hindpaws.
Figure 3: Mutation-dependent pure motor or sensorimotor axonal loss and denervation of neuromuscular junctions in mice expressing mutant HSPB1.
Figure 4: Mutant HSPB1 mice show axonal transport defects and decreased acetylated tubulin levels.
Figure 5: HDAC6 inhibition rescues axonal transport defects and restores the CMT2 phenotype.
Figure 6: TSA or tubastatin A treatment leads to muscle reinnervation and rescues axonal transport defects.

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Acknowledgements

We thank L. Almeida-Souza and S. Janssens for their constructive comments and the Molecular Small Animal Imaging Centre (MoSAIC, K.U. Leuven) for the use of the Catwalk system. We are grateful to B. Weynants and N. Hersmus for the technical assistance. We thank R. Mazitschek and J. Bradner (Dana-Farber Cancer Institute, Harvard Medical School) for kindly giving us tubacin. The research to create tubastatin A was supported by an American Chemical Society Fellowship and by the International Rett Syndrome Foundation. We thank J. H. Kalin for helping us with the creation of the HDAC6 homology model. This work was supported by grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen), the University of Leuven (K.U. Leuven, GOA/12/014 and OT/10/046), the Belgian government (Interuniversity Attraction Poles, programme P6/43 of the Belgian Federal Science Policy Office), the Association Belge contre les Maladies neuro-Musculaires, the Association Française contre les Myopathies (projects 13169 and 14471), the Frick Foundation for Amyotrophic Lateral Sclerosis Research, the Muscular Dystrophy Association and the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867). C.d.Y. is supported by the Agency for Innovation by Science and Technology in Flanders. P.V.D. is a clinical researcher, and J.I. is a postdoctoral fellow of the FWO-Vlaanderen. W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders.

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Authors and Affiliations

  1. Vesalius Research Center, VIB and K.U. Leuven, Campus Gasthuisberg, Leuven, Belgium

    Constantin d'Ydewalle, Jyothsna Krishnan, Driss M Chiheb, Philip Van Damme, Wim Robberecht & Ludo Van Den Bosch

  2. Laboratory for Neurobiology, K.U. Leuven, Leuven, Belgium

    Constantin d'Ydewalle, Jyothsna Krishnan, Driss M Chiheb, Philip Van Damme, Wim Robberecht & Ludo Van Den Bosch

  3. Department of Neurology, University Hospital Leuven, Leuven, Belgium

    Philip Van Damme & Wim Robberecht

  4. Department of Molecular Genetics, Peripheral Neuropathy Group, VIB and University of Antwerp, Antwerp, Belgium

    Joy Irobi & Vincent Timmerman

  5. Neurogenetics Laboratory, Institute Born Bunge, Antwerp, Belgium

    Joy Irobi & Vincent Timmerman

  6. Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois, USA

    Alan P Kozikowski

  7. Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal Disorders, K.U. Leuven, Leuven, Belgium

    Pieter Vanden Berghe

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  1. Constantin d'Ydewalle
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Contributions

C.d.Y. planned and performed all the experiments. J.K. developed the transgenic mice and did the initial characterization of the phenotype. D.M.C. provided technical support. P.V.D. assisted with the electrophysiological experiments, J.I. provided the original HSPB1 constructs, A.P.K. provided tubastatin A and P.V.B. helped with the axonal transport measurements. P.V.B., P.V.D., J.I., A.P.K., V.T. and W.R. provided ideas for the project and participated in writing the paper. L.V.D.B. planned and supervised the experiments. C.d.Y. and L.V.D.B. wrote the paper.

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Correspondence to Ludo Van Den Bosch.

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d'Ydewalle, C., Krishnan, J., Chiheb, D. et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1–induced Charcot-Marie-Tooth disease. Nat Med 17, 968–974 (2011). https://doi.org/10.1038/nm.2396

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