https://academic.oup.com/brain/article/141/3/673/4838963
https://www.ncbi.nlm.nih.gov/pubmed/29415205
HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.
Brain. 2018 Mar 1;141(3):673-687. doi: 10.1093/brain/awx375.
HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.
Benoy V1,2, Van Helleputte L1,2, Prior R1,2, d’Ydewalle C1,2, Haeck W1,2, Geens N1,2, Scheveneels W1,2, Schevenels B1,2, Cader MZ3,4, Talbot K3, Kozikowski AP5, Vanden Berghe P6, Van Damme P1,2,7, Robberecht W1,2,7, Van Den Bosch L1,2.
Author information
Abstract
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.
PMID: 29415205 PMCID: PMC5837793 DOI: 10.1093/brain/awx375
