Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

• Published in: Frontiers in molecular neuroscience Vol. 13; p. 78
• Main Authors: Xue, Yuan Chao, Ng, Chen Seng, Xiang, Pinhao, Liu, Huitao, Zhang, Kevin, Mohamud, Yasir, Luo, Honglin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 29.05.2020; Frontiers Media S.A
• Subjects: aggregation; Amyotrophic lateral sclerosis; Clinical trials; FLI-1 protein; gene mutations; Genetic analysis; Homeostasis; Kinases; Localization; mRNA stability; Mutation; Neurodegeneration; Neuroscience; nucleocytoplasmic transport; Phase transitions; Polyadenylation; Post-translation; Protein turnover; RNA metabolism; RNA-binding protein; RNA-binding proteins; Splicing; Transient ischemic attack; nucleocytoplasmic transport; RNA-binding proteins; aggregation; gene mutations; RNA metabolism
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2020.00078

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 , , , , , , , , and , 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.