Parakh Sonam, Atkin Julie D
Department of Biomedical Sciences, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, NSW, 2109 Australia.
Department of Biomedical Sciences, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, NSW, 2109 Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia.
Brain Res. 2016 Oct 1;1648(Pt B):633-649. doi: 10.1016/j.brainres.2016.04.010. Epub 2016 Apr 7.
Protein misfolding leads to the formation of aggregated proteins and protein inclusions, which are associated with synaptic loss and neuronal death in neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord. Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72. Chaperone proteins, including heat shock proteins (Hsp׳s) and the protein disulphide isomerase (PDI) family, assist in protein folding and therefore can prevent protein misfolding, and have been implicated as being protective in ALS. In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention. This article is part of a Special Issue entitled SI:ER stress.
蛋白质错误折叠会导致聚集蛋白和蛋白包涵体的形成，这与神经退行性疾病中的突触丧失和神经元死亡有关。肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，主要影响大脑、脑干和脊髓中的运动神经元。在ALS中，有几种蛋白质会错误折叠，并且在遗传或病理上与之相关，包括超氧化物歧化酶1（SOD1）、Tar DNA结合蛋白43（TDP - 43）、泛素连接蛋白2、p62、VCP以及由C9ORF72中重复扩增的非常规重复相关非ATG翻译产生的二肽重复蛋白。伴侣蛋白，包括热休克蛋白（Hsp）和蛋白质二硫键异构酶（PDI）家族，协助蛋白质折叠，因此可以防止蛋白质错误折叠，并且在ALS中被认为具有保护作用。在这篇综述中，我们概述了当前关于ALS中蛋白质错误折叠和聚集的分子机制的文献，以及伴侣蛋白作为治疗干预潜在靶点的作用。本文是名为“SI：内质网应激”的特刊的一部分。
