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.

对肌萎缩性脊髓侧索硬化症 (ALS) 患者的遗传分析表明，编码许多 RNA 结合蛋白 (RBP) 的基因突变之间存在密切关联，包括 TARDBP、FUS、hnRNPA1、hnRNPA2B1、MATR3、ATXN2、TAF15、TIA-1 和EWSR1 和疾病发作/进展。 RBP 是一组进化上保守的蛋白质，参与 RNA 代谢的多个步骤，包括剪接、多聚腺苷酸化、mRNA 稳定性、定位和翻译。由于基因突变、核质运输受损、翻译后修饰 (PTM)、聚集和异常 RNA 灶的隔离，RBP 失调已被证明与神经变性和 ALS 的发展有关。虽然失调的 RBP 导致 ALS 的确切机制仍然难以捉摸，但新出现的证据支持这样的观点，即这些 ALS 相关 RBP 的功能丧失和/或毒性功能的增加通过促进异常蛋白在疾病发病机制中发挥着重要作用。相互作用，导致RNA代谢异常，并干扰核糖核蛋白颗粒动力学和相变。在这篇综述文章中，我们总结了目前关于 RBP 失调的分子机制以及缺陷 RBP 在 ALS 发展过程中对细胞稳态的影响的知识。本综述还讨论了正在进行的针对 RBP 和/或相关过程的临床试验的策略。