ALS相关突变型σ1R的激活促进大鼠施旺细胞RSC96的凋亡

发布时间：2018-04-01 23:31

本文选题：肌萎缩性侧索硬化症　切入点：Sigma-型受体　出处：《复旦学报(自然科学版)》2017年06期

【摘要】：肌萎缩性侧索硬化症(ALS)是一种渐进的致命的神经退行性疾病,症状为运动神经元损失所导致的肌肉萎缩和痉挛,大部分病人最后死于呼吸衰竭.对其致病机理的研究主要集中于对神经元的影响,而对施旺细胞在其中的作用至今仍未有报道.之前研究发现在一个青少年发病的ALS家族中,SIGMAR1基因编码区的一个碱基存在错位突变,该突变使Sigma-1型受体(σ1R)的102位氨基酸由谷氨酸(E)突变为谷氨酰胺(Q).本文通过在大鼠施旺细胞系(RSC96细胞)中过表达野生型及突变型σ1R来研究该突变对RSC96细胞凋亡的影响.实验结果表明在毒胡萝卜素(Thapsigargin)诱导的内质网压力和σ1R激动剂PRE084的刺激下,突变型σ1R使施旺细胞更倾向于凋亡,失去了对胞质Ca~(2+)调节的能力,并且对ADAM10具有更强的抑制作用.本研究提示σ1R突变也可能通过施旺细胞对ALS的病理过程起到作用.
[Abstract]:ALS is a progressive and fatal neurodegenerative disease characterized by muscle atrophy and spasm caused by loss of motor neurons. Most patients die of respiratory failure.The pathogenetic mechanism of Schwann cells is mainly focused on its effect on neurons, but the role of Schwann cells in it has not been reported.Previous studies have found a translocation mutation in the coding region of the SIGMAR1 gene in a teenage ALS family, which mutated the 102-amino acid of the Sigma-1 receptor (蟽 1R) from glutamate to glutamine.The effect of this mutation on apoptosis of RSC96 cells was studied by overexpression of wild type 蟽 1R and mutant 蟽 1R in rat Schwann cell line RSC96.The results showed that the mutant 蟽 1R induced endoplasmic reticulum (ER) pressure and 蟽 1R agonist PRE084 stimulated Schwann cells to apoptosis, lost the ability to regulate cytoplasmic Ca~(2, and had a stronger inhibitory effect on ADAM10.This study suggests that 蟽 1R mutation may also play a role in the pathological process of ALS through Schwann cells.
【作者单位】：复旦大学生命科学学院;复旦大学发育生物学研究院;复旦大学附属妇产科医院生殖发育研究院;
【基金】：国家重点基础研究发展计划(2013CB945404) 上海市科委重点创新项目(14JC1401000)
【分类号】：R744.8

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