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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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.
The authors declare no competing financial interests.
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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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