Faculty of Medicine, The University of New South Wales, Kensington, Sydney, NSW 2033, Australia.
Iggy Get Out, Neurodegenerative Disease Section, Darlinghurst, Sydney, NSW 2010, Australia.
Int J Mol Sci. 2020 May 14;21(10):3464. doi: 10.3390/ijms21103464.
Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)-including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)-have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1-a non-RBP commonly associated with familial ALS (fALS)-exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research.
超越理解肌萎缩侧索硬化症（ALS）的传统方法，最近在 RNA 结合蛋白（RBPs）中的多项研究——包括反式激活反应 DNA 结合蛋白（TDP-43）和融合肉瘤（FUS）——引起了人们对其功能和类朊病毒特性的兴趣。鉴于它们作为高度异质疾病的显著特征，这促使我们重新审视这些蛋白质之间的特定功能相互关系，特别是由于病理 SOD1——一种通常与家族性 ALS（fALS）相关的非 RBP——表现出与这些 RBP 相似的特性，包括潜在的 RNA 调节能力。此外，TDP-43、FUS 和 SOD1 的细胞质定位、聚集和共聚集可被视为类似于其他神经退行性疾病（NDs）的蛋白质病，与 RNA 剪接、运输和稳定性的破坏密切相关。近年来，microRNAs（miRNAs）也越来越多地被牵连到疾病中，它们具有更大的意义，因为它们是疾病病理学中 RNA 代谢的主要调节剂。然而，对于这些蛋白质的作用及其如何被 miRNA 调节知之甚少，这将为 ALS 发病机制提供机制见解。本综述旨在讨论 TDP-43、FUS 和 SOD1 的最新进展，以构建 ALS 网络病理生理学的详细快照，同时旨在突出可能的新治疗靶点，以指导未来的研究。
