HDAC6 inhibition promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice

Experimental Neurology
Cristina PicciBrett Langley

Abstract

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts...Continue Reading

Citations

Aug 29, 2020·Molecular Neurobiology·Roberta De GioiaFederica Rizzo
May 3, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Dion A PaulAbdul Qayyum Rana
Oct 10, 2020·European Journal of Medicinal Chemistry·Maurício T TavaresSida Shen
Nov 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sravani PulyaBalaram Ghosh
Jan 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Maria Elena PeroFrancesca Bartolini
Dec 31, 2020·Cells·Patrizia LoPresti
May 5, 2021·Annals of Clinical and Translational Neurology·Elena AbatiStefania Corti
May 26, 2021·Expert Review of Neurotherapeutics·Chiara PisciottaDavide Pareyson
Jul 27, 2021·Glia·Alessandro MorminoStefano Garofalo
Oct 5, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Brett A McCray, Steven S Scherer

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