ALS相关突变型σ1R的激活促进大鼠施旺细胞RSC96的凋亡

Activation ofσ1R Mutation Related to ALS Promotes the Apoptosis of Rat Schwann Cells RSC96

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.

Amyotrophic Lateral Sclerosis（ALS）is a progressive neurodegenerative disease characterized by loss of upper and lower motor neurons in the brain and spinal cord,leading to amyotrophy and spasm and ultimately death from respiratory failure.Most studies focused on motor neurons to understand the pathogenesis of this disease,while none have tried to explore the role of Schwann cells in the progression of ALS.Previous study reported a mutation of SIGMAR1 gene in a family of juvenile ALS.The 102 nd amino acid of mutated sigma-1 Receptor（σ1 R）turned to be glutamine（Q）instead of glutamic acid（E）.We overexpressed wild-type or mutatedσ1 Rin rat Schwann cells（RSC96 cell line）to explore the effects of this mutation on apoptosis of RSC96 cells.Our results showed that under Thapsigargin-induced ER stress and stimulation of PRE084（agonist ofσ1 R）,overexpression of mutatedσ1 Rpromoted apoptosis in RSC96 cells,lost the ability to inhibit the upregulation of cytoplasmic Ca2＋,and exerted stronger inhibition ofADAM10 activity.Our study suggested a possible role of Schwann cells in the pathogenesis of ALS through mutatedσ1 R.