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Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot-Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated α-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased α-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that α-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease.

Original publication

DOI

10.1093/brain/awx375

Type

Journal article

Journal

Brain

Publication Date

01/03/2018

Volume

141

Pages

673 - 687

Keywords

Animals, Axonal Transport, Cells, Cultured, Charcot-Marie-Tooth Disease, Disease Models, Animal, Enzyme Inhibitors, Ganglia, Spinal, Glycine-tRNA Ligase, Histone Deacetylase 6, Hydroxamic Acids, Indoles, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons, Mutation, Neural Conduction, Neuromuscular Junction, Psychomotor Performance, RNA, Small Interfering, Tubulin