Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Centre for Motor Neuron Disease Research, Macquarie University, Sydney, NSW, Australia; Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, NSW, 2006, Australia.
The Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, Faculty of Science and Engineering, Macquarie University, North Ryde, NSW, Australia.
Int J Biochem Cell Biol. 2020 Sep;126:105821. doi: 10.1016/j.biocel.2020.105821. Epub 2020 Aug 3.
Mutations in fused-in-sarcoma (FUS) and TAR DNA binding protein-43 (TDP-43; TARDBP) are known to cause the severe adult-onset neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Proteinopathy caused by cellular stresses such as endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial stress and proteasomal stress and the formation of stress granules (SGs), cytoplasmic aggregates and inclusions is a hallmark of ALS. FUS and TDP-43, which are DNA/RNA binding proteins that regulate transcription, RNA homeostasis and protein translation are implicated in ALS proteinopathy. Disease-causing mutations in FUS and TDP-43 cause sequestration of these proteins and their interacting partners in the cytoplasm, which leads to aggregation. This mislocalization and formation of aggregates and SGs is cytotoxic and a contributor to neuronal death. We explore how loss-of-nuclear-function and gain-of-cytoplasmic function mechanisms that affect FUS and TPD-43 localization can generate a 'stressed out' neuronal pathology and proteinopathy that drives ALS progression.
融合肉瘤（FUS）和 T 细胞受体（TAR）DNA 结合蛋白-43（TDP-43；TARDBP）的突变已知会导致严重的成人发病神经退行性疾病肌萎缩侧索硬化症（ALS）。由内质网（ER）应激、氧化应激、线粒体应激和蛋白酶体应激等细胞应激引起的蛋白病以及应激颗粒（SGs）、细胞质聚集体和内含物的形成是 ALS 的标志。FUS 和 TDP-43 是调节转录、RNA 稳态和蛋白质翻译的 DNA/RNA 结合蛋白，与 ALS 蛋白病有关。FUS 和 TDP-43 的致病突变导致这些蛋白及其相互作用伙伴在细胞质中的隔离，从而导致聚集。这种定位错误以及聚集体和 SG 的形成具有细胞毒性，是神经元死亡的原因之一。我们探讨了影响 FUS 和 TPD-43 定位的核功能丧失和胞质功能获得机制如何产生“压力过大”的神经元病理学和蛋白病，从而推动 ALS 的进展。
