Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have revealed a strong association between mutations in genes encoding many RNA-binding proteins (RBPs), including TARDBP, FUS, hnRNPA1, hnRNPA2B1, MATR3, ATXN2, TAF15, TIA-1, and EWSR1, and disease onset/progression. RBPs are a group of evolutionally conserved proteins that participate in multiple steps of RNA metabolism, including splicing, polyadenylation, mRNA stability, localization, and translation. Dysregulation of RBPs, as a consequence of gene mutations, impaired nucleocytoplasmic trafficking, posttranslational modification (PTM), aggregation, and sequestration by abnormal RNA foci, has been shown to be involved in neurodegeneration and the development of ALS. While the exact mechanism by which dysregulated RBPs contribute to ALS remains elusive, emerging evidence supports the notion that both a loss of function and/or a gain of toxic function of these ALS-linked RBPs play a significant role in disease pathogenesis through facilitating abnormal protein interaction, causing aberrant RNA metabolism, and by disturbing ribonucleoprotein granule dynamics and phase transition. In this review article, we summarize the current knowledge on the molecular mechanism by which RBPs are dysregulated and the influence of defective RBPs on cellular homeostasis during the development of ALS. The strategies of ongoing clinical trials targeting RBPs and/or relevant processes are also discussed in the present review.

对肌萎缩性侧索硬化症（ALS）患者的遗传分析显示，编码许多RNA结合蛋白（RBP）的基因的突变之间有很强的联系，包括 TARDBP， FUS， hnRNPA1， hnRNPA2B1， MATR3， ATXN2， TAF15， TIA-1和 EWSR1，以及疾病的发作/进展。RBP是一组进化保守的蛋白质，它们参与RNA代谢的多个步骤，包括剪接，聚腺苷酸化，mRNA稳定性，定位和翻译。RBPs的失调是基因突变，核质运输受损，翻译后修饰（PTM），聚集和异常RNA病灶引起的螯合的结果，已被证明与神经变性和ALS的发展有关。尽管失调的RBP促成ALS的确切机制仍然难以捉摸，但新出现的证据支持以下观点：这些ALS连接的RBP的功能丧失和/或毒性功能的获得均通过促进异常蛋白在疾病发病中发挥重要作用相互作用，导致异常的RNA代谢，并干扰核糖核蛋白颗粒的动力学和相变。在这篇综述文章中，我们总结了有关ALS发育过程中RBP失调的分子机制以及缺陷性RBP对细胞稳态的影响的当前知识。在本综述中还讨论了针对RBP和/或相关过程的正在进行的临床试验的策略。