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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.

Author information

1
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Research Institute for Neuroscience & Disease (LIND), Leuven, Belgium.
2
VIB - Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
3
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
4
The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
5
Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, USA.
6
Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.
7
University Hospitals Leuven, Department of Neurology, Leuven, Belgium.

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
[Indexed for MEDLINE]
Free PMC Article

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