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

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 GARS1^P724H 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.

SUBMITTER: Smith AST

PROVIDER: S-EPMC8849597 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Smith Alec S T AST Kim Jong Hyun JH Chun Changho C Gharai Ava A Moon Hyo Won HW Kim Eun Young EY Nam Soo Hyun SH Ha Nina N Song Ju Young JY Chung Ki Wha KW Doo Hyun Myung HM Hesson Jennifer J Mathieu Julie J Bothwell Mark M Choi Byung-Ok BO Kim Deok-Ho DH

Advanced biology 20211226 2

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 deficien ...[more]

PMID: 34958183

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Project description:Background: Electrophysiological examination plays an important role in the diagnosis of X-linked Charcot-Marie-Tooth disease (CMTX1) with transient central nervous system deficits. However, the electrophysiological features are seldom reported. Methods: We reviewed and analyzed published reports to determine the electrophysiological features of CMTX1 patients with transient central nervous system deficits. Results: A total of 21 CMTX1 patients with transient central nervous system deficits were found in 17 published case reports/series. The age of onset ranged from 0.5 to 18 years (mean 12.02 ± 0.78 years). All patients were male. Recurrent episodes of central nervous system deficits were reported in all 21 cases and resolved in periods ranging from several minutes to 3 days. All 20 patients who had MRIs at presentation had bilaterally symmetrical abnormal T2/Diffusion signals in the white matter without enhancement of gadolinium. All subsequent MRIs showed improvement or were within normal limits. The median motor nerve conduction velocity (MNCV), motor latencies, and compound muscle action potential (CMAP) amplitude were the most commonly measurable electrophysiological parameters (85.7%). All cases that had MNCV at presentation had slower and significantly decreased MNCV compared with the normal value (34.1 ± 1.10 m/s vs. 46.8±2.05 m/s, P < 0.0001; 95% CI, -17.4 to -7.92). The average variations of MNCV in median nerve, ulnar nerve, peroneal nerve, and tibial nerve were 22.0 ± 5.96%, 27.6 ± 11.9%, 25.9 ± 4.36%, and 27.3 ± 4.30%, respectively. All cases with measured sensory nerve conduction velocity (SNCV) at presentation had slower and significantly decreased SNCV compared with the normal value (35.3 ± 1.33 m/s vs. 47.7 ± 2.40 m/s, P < 0.001; 95% CI -18.2 to -6.46). The average variations of SNCV in median nerve, ulnar nerve, and sural nerve were 19.9 ± 8.24%, 25.2 ± 7.75%, and 23.2 ± 3.95%, respectively. Conclusion: This case series serves as a reminder that electrophysiological examination should be included in the diagnosis of recurrent and episodic neurological deficit with white matter lesions. Median MNCV is a sensitive and valuable parameter to support the diagnosis of CMTX1 with transient central nervous system deficits.

Dataset Information

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

Publications

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

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