Endoplasmic reticulum stress intolerance in EIF2B3 mutant oligodendrocytes is modulated by depressed autophagy
Endoplasmic reticulum stress intolerance in EIF2B3 mutant oligodendrocytes is modulated by depressed autophagy
复制标题
DOI：
10.1016/j.braindev.2015.11.002
复制
发表时间：
2016-05-01
影响因子：
1.7
通讯作者：
Wu, Ye
中科院分区：
文献类型：
--
作者：
Chen, Na;Dai, Lifang;Wu, Ye
目的：真核生物翻译起始因子2B （eIF2B）是蛋白质合成起始的重要因子。EIF2BI-5编码的eIF2B突变可导致致死性脑白质病（VWM）。先前的研究表明，内质网应激（ERS）后不适当的未折叠蛋白反应（UPR）激活参与了疾病的发病机制。自噬是ERS后重要的代偿途径，本研究对其进行了分析。方法：检测转染EIF2B3-c的少突胶质细胞系对ERS的耐受性差异，细胞活力和凋亡率。1037T>C或野生型。测定各组间自噬通量。自噬诱导剂和抑制剂被用来鉴定自噬在突变少突胶质细胞中的作用。结果：我们证实突变EIF2B3的少突胶质细胞对ERS的耐受性低于野生型，细胞活力下降，凋亡率增加。在基线条件下和ERS刺激后，突变少突胶质细胞的自噬通量被抑制。自噬相关基因（Atg） 3和Atg 7的表达降低参与了自噬通量的抑制。经自噬诱导剂预处理的突变少突胶质细胞，尽管有ERS诱导，但细胞活力稳定，凋亡减少。抑制剂加重细胞凋亡和活力下降。结论：转染突变型EIF2B3的少突胶质细胞对ERS的耐受性低于野生型。在基线和ERS刺激后，突变细胞的自噬通量被抑制。在EIF2B3突变型少突胶质细胞中，不当抑制自噬在ERS易感性中起作用。(C) 2015日本儿童神经病学学会。Elsevier B.V.版权所有。
Objective: Eukaryotic translation initiation factor 2B (eIF2B) is an essential factor for the initiation of protein synthesis. Mutations in eIF2B encoded by EIF2BI-5 cause a lethal leukoencephalopathy vanishing white matter disease (VWM). Previous studies have suggested that an improper activated unfolded protein response (UPR) after endoplasmic reticulum stress (ERS) contributed to the pathogenesis of the disease. Autophagy, an important compensatory pathway after ERS, was analyzed in this study.Methods: To determine the tolerance differences to ERS, cell viability and apoptosis rates were detected in oligodendrocyte cell lines transfected with EIF2B3-c.1037T>C or the wild type. Autophagy flux was measured between groups. Autophagy inducers and inhibitors were used to identify the role of autophagy in the mutant oligodendrocytes.Results: We confirmed that oligodendrocytes with mutant EIF2B3 was less tolerant to ERS than the wild type, with decreased cell viability and increased apoptosis rates. Autophagy flux was depressed in mutant oligodendrocytes under baseline condition and after ERS stimulation. Reduced expression of autophagy related gene (Atg) 3 and Atg 7 were involved in the depression of autophagy flux. The mutant oligodendrocytes pretreated with autophagy inducers showed stable cell viability and decreased apoptosis despite ERS induction, whereas the autophagy. inhibitors aggravated cell apoptosis and viability declination.Conclusions: Oligodendrocytes transfected with mutant EIF2B3 was less tolerant to ERS than the wild type. Depressed autophagy flux was observed in the mutant cells at baseline and after ERS stimulation. Improperly depressed autophagy played a role in the susceptibility to ERS in EIF2B3 mutant oligodendrocytes. (C) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.