HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D).
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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DOI：
10.1002/adbi.202101308
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发表时间：
2022-03
期刊：
影响因子：
3.7
通讯作者：
Kim DH
中科院分区：
文献类型：
--
作者：
Smith AST;Kim JH;Chun C;Gharai A;Moon HW;Kim EY;Nam SH;Ha N;Song JY;Chung KW;Doo HM;Hesson J;Mathieu J;Bothwell M;Choi BO;Kim DH
腓骨肌萎缩症2D型（CMT 2D）是由编码甘氨酰-tRNA合成酶（GARS 1）的基因突变引起的遗传性周围神经病变。在此，描述了携带GARS 1突变的CMT 2D的基于人诱导多能干细胞（hiPSC）的模型及其用于鉴定适于治疗功效筛选的预测性生物标志物的用途。含有从这条线产生的脊髓运动神经元的培养物表现出网络活动，其特征在于自发动作电位放电和突发放电行为的显著缺陷。该结果与从携带GARS 1 P724 H突变的患者中收集的临床数据相匹配，并且与乙酰化α-微管蛋白水平和轴突内线粒体运动的显著降低相结合。用HDAC 6抑制剂tubastatin A和CKD 504处理，改善了这些细胞中的线粒体运动和α-微管蛋白乙酰化。此外，CKD 504治疗增强了群体水平的电生理活性，突出了其作为CMT 2D有效治疗的潜力。携带GARS 1突变的人iPSC衍生的脊髓神经元表现出线粒体转运和电生理缺陷。异常的GARS 1-HDAC 6蛋白相互作用存在于GARS 1 P234 KY神经元中，而不是GARS 1 P724 H神经元中。在两种突变基因型中，HDAC 6抑制改善线粒体转运和电生理功能。结果表明HDAC 6抑制可以治疗腓骨肌萎缩症（2D型），而且观察到的神经元功能的改善通过非疾病相关机制发生。
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 exhibited network activity marked by significant deficiencies in spontaneous action potential firing and burst fire behavior. This result matched clinical data collected from a patient bearing a GARS1P724H mutation and was coupled with significant decreases in acetylated α-tubulin levels and mitochondrial movement within axons. Treatment with HDAC6 inhibitors, tubastatin A and CKD504, improved mitochondrial movement and α-tubulin acetylation in these cells. Furthermore, CKD504 treatment enhanced population-level electrophysiological activity, highlighting its potential as an effective treatment for CMT2D. Human iPSC-derived spinal neurons bearing mutations in GARS1 exhibit mitochondrial transport and electrophysiological deficits. Aberrant GARS1-HDAC6 protein interactions are present in GARS1P234KY, but not GARS1P724H, neurons. In both mutant genotypes, HDAC6 inhibition improves mitochondrial transport and electrophysiological function. Results suggest that HDAC6 inhibition could be therapeutic for Charcot-Marie-Tooth disease (type 2D), but also that observed improvements in neuronal function occur via non-disease related mechanisms.
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影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
9.8
作者：
Bhumbra GS;Beato M
通讯作者：
Beato M
影响因子：
6
作者：
Chiappalone, M;Novellino, A;van Pelt, J
通讯作者：
van Pelt, J
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED
DOI：
10.1093/brain/awx375
发表时间：
2018-03-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Benoy V;Van Helleputte L;Prior R;d'Ydewalle C;Haeck W;Geens N;Scheveneels W;Schevenels B;Cader MZ;Talbot K;Kozikowski AP;Vanden Berghe P;Van Damme P;Robberecht W;Van Den Bosch L
通讯作者：
Van Den Bosch L