Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation

未折叠蛋白反应，包括应激传感器激酶、伴侣蛋白和凋亡介质的诱导，参与了与突变型Cu/Zn超氧化物歧化酶（SOD1）和散发性ALS相关的家族性肌萎缩性侧索硬化症（ALS）模型。我们假设内质网驻留因子Derlin-1在SOD1突变引起的错误折叠蛋白的调控中起关键作用。我们发现，Derlin-1过表达通过抑制内质网应激途径因子（免疫球蛋白结合蛋白、激活转录因子6p50和C/EBP同源蛋白）的激活，降低突变体sod1诱导的细胞毒性，提高细胞活力。有趣的是，外源性Derlin-1导致转染细胞中SOD1突变体的数量减少，而野生型SOD1的数量减少较少。野生型和突变型SOD1细胞微粒体部分SOD1蛋白表达降低。我们的研究结果表明，Derlin-1通过促进SOD1蛋白的蛋白酶体和自噬体降解来调节SOD1的翻转，而不是通过降低突变体SOD1 mRNA的水平。深入了解德林-1对SOD1突变体的影响可能会促进ALS相关运动神经元变性治疗的进展。

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.