Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation
Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation
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DOI：
10.1016/j.neuint.2010.12.010
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Uchino, Makoto
中科院分区：
文献类型：
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作者：
Mori, Akira;Yamashita, Satoshi;Uchino, Makoto
未折叠的蛋白质反应，包括诱导应激传感器激酶，分子伴侣和凋亡介质，参与了与突变型Cu/Zn超氧化物歧化酶（SOD 1）和散发性ALS相关的家族性肌萎缩侧索硬化症（ALS）模型。我们推测内质网驻留因子Derlin-1在突变SOD 1引起的错误折叠蛋白的调节中起着关键作用。我们发现，Derlin-1过表达降低突变SOD 1诱导的细胞毒性，并通过抑制ER应激途径因子（免疫球蛋白结合蛋白，激活转录因子6 p50和C/EBP同源蛋白）的激活来增加细胞活力。有趣的是，外源性Derlin-1导致转染细胞中突变型SOD 1的量减少，野生型SOD 1的量减少较少。在野生型和突变型SOD 1细胞的微粒体部分中观察到SOD 1蛋白表达降低。我们的研究结果表明，Derlin-1通过促进SOD 1蛋白的蛋白酶体和自噬体降解来调节SOD 1的翻转，但不是通过降低突变SOD 1 mRNA水平。深入了解Derlin-1对突变型SOD 1的影响可能会促进与ALS相关的运动神经元变性治疗的进展。(C)2010爱思唯尔有限公司保留所有权利。
Unfolded protein responses, including induction of stress sensor kinases, chaperones, and apoptotic mediators, are involved in the familial amyotrophic lateral sclerosis (ALS) model related to mutant Cu/Zn superoxide dismutase (SOD1) and sporadic ALS. We hypothesized that the endoplasmic reticulum-resident factor Derlin-1 plays a pivotal role in the regulation of misfolded proteins evoked by mutant SOD1. We show that Derlin-1 overexpression reduced mutant SOD1-induced cell toxicity and increased cell viability by suppressing the activation of the ER stress pathway factors: immunoglobulin-binding protein, activating transcription factor 6 p50, and C/EBP homologous protein. Interestingly, exogenous Derlin-1 resulted in a decrease in the amount of mutant SOD1, and a lesser decrease in that of wild-type SOD1, in transfected cells. Reduced SOD1 protein expression was observed in the microsomal fraction of wild-type and mutant SOD1 cells. Our results indicate that Derlin-1 regulates the turn over of SOD1 by promoting the proteasomal and autophagosomal degradation of SOD1 protein, but not by decreasing mutant SOD1 mRNA levels. Insights into the effects of Derlin-1 on mutant SOD1 may facilitate advancements in the treatment of motor neuron degeneration associated with ALS. (C) 2010 Elsevier Ltd. All rights reserved.