HDAC6型
诱导多能干细胞
电生理学
生物
复合肌肉动作电位
干细胞
乙酰化
突变
神经科学
细胞生物学
组蛋白脱乙酰基酶
组蛋白
遗传学
基因
胚胎干细胞
作者
Alec S.T. Smith,Jong Hyun Kim,Changho Chun,Ava Gharai,Heui Soo 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
标识
DOI:10.1002/adbi.202101308
摘要
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.
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