HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D)

Alec S.T. Smith, Jong Hyun Kim, Changho Chun, Ava Gharai, Hyo Won Moon, Eun Young Kim, Soo Hyun Nam, Nina Ha, Ju Young Song, Ki Wha Chung, Hyun Myung Doo, Jennifer Hesson, Julie Mathieu, Mark Bothwell, Byung Ok Choi, Deok Ho Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Charcot-Marie-Tooth disease type 2D (CMT2D), is a hereditary peripheral neuropathy caused by mutations in the gene encoding glycyl-tRNA synthetase (GARS1). Here, human induced pluripotent stem cell (hiPSC)-based models of CMT2D bearing mutations in GARS1 and their use for the identification of predictive biomarkers amenable to therapeutic efficacy screening is described. Cultures containing spinal cord motor neurons generated from this line exhibit network activity marked by significant deficiencies in spontaneous action potential firing and burst fire behavior. This result matches clinical data collected from a patient bearing a GARS1P724H mutation and is coupled with significant decreases in acetylated α-tubulin levels and mitochondrial movement within axons. Treatment with histone deacetylase 6 inhibitors, tubastatin A and CKD504, improves mitochondrial movement and α-tubulin acetylation in these cells. Furthermore, CKD504 treatment enhances population-level electrophysiological activity, highlighting its potential as an effective treatment for CMT2D.

Original languageEnglish (US)
Article number2101308
JournalAdvanced Biology
Volume6
Issue number2
DOIs
StatePublished - Feb 2022

Keywords

  • Charcot-Marie-Tooth disease
  • axonopathy
  • drug screening
  • electrophysiology
  • induced pluripotent stem cell
  • neurodegeneration

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Biomedical Engineering
  • Biomaterials

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