Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons. Between 12 and 20% of inherited cases and approximately 1–2% of all cases are caused by mutations in the gene encoding dismutase 1 (SOD1). Mutant SOD1 A4V (alanine to valine) induces endoplasmic reticulum (ER) stress, which is increasingly implicated as a pathway to motor neuron degeneration and death in ALS. However, it remains unclear how ER stress is induced by mutant SOD1 A4V. Previous studies have established that it is induced early in pathophysiology and it precedes the formation of mutant SOD1 inclusions. SOD1 contains four cysteine residues, two of which form an intra-subunit disulphide bond involving Cys-57 and Cys-146. The remaining two cysteines, Cys-6 and Cys-111, remain unpaired and have been implicated in mutant SOD1 aggregation. In this study, we examined the relationship between the SOD1 A4V cysteine residues and aggregation, ER stress induction and toxicity. We report here that mutation of Cys-6 and Cys-111 in mutant SOD1 A4V, but not Cys-57 or Cys-146, ameliorates ER stress, inclusion formation and apoptosis in neuronal cell lines. These results imply that protein misfolding, induced by Cys-6 and Cys-111, is required for these pathological events in neuronal cells.

中文翻译：

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突变型超氧化物歧化酶1（SOD1）A4V中的半胱氨酸（Cys）残基Cys-6和Cys-111是诱导肌萎缩性侧索硬化的内质网应激所必需的。

肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，其特征在于运动神经元变性。在12％至20％的遗传病例中，大约所有病例的1-2％是由编码歧化酶1（SOD1）的基因突变引起的。突变的SOD1 A4V（丙氨酸至缬氨酸）诱导内质网（ER）应激，越来越多地被认为是导致ALS运动神经元变性和死亡的途径。但是，尚不清楚突变体SOD1 A4V如何诱导ER应激。先前的研究已经确定，它是在病理生理学中被早期诱导的，并且它在突变型SOD1内含物形成之前就已经存在。SOD1包含四个半胱氨酸残基，其中两个形成涉及Cys-57和Cys-146的亚单位内二硫键。剩下的两个半胱氨酸Cys-6和Cys-111 保持未配对状态，并与突变SOD1聚集有关。在这项研究中，我们检查了SOD1 A4V半胱氨酸残基与聚集，内质网应激诱导和毒性之间的关系。我们在这里报告，突变体SOD1 A4V中的Cys-6和Cys-111突变，而不是Cys-57或Cys-146，改善了ER应激，神经元细胞系的内含物形成和凋亡。这些结果暗示由Cys-6和Cys-111诱导的蛋白质错误折叠对于神经元细胞中的这些病理事件是必需的。