Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

Yuan Chao Xue; Chen Seng Ng; Pinhao Xiang; Huitao Liu; Kevin Zhang; Yasir Mohamud; Honglin Luo

doi:10.3389/fnmol.2020.00078

Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

Front Mol Neurosci. 2020 May 29:13:78. doi: 10.3389/fnmol.2020.00078. eCollection 2020.

Authors

Yuan Chao Xue^{1

2}, Chen Seng Ng^{1

2}, Pinhao Xiang^{1

2}, Huitao Liu^{1

3}, Kevin Zhang^{1

2}, Yasir Mohamud^{1

2}, Honglin Luo^{1

2}

Affiliations

¹ Centre for Heart and Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.
² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.

Abstract

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.

Keywords: RNA metabolism; RNA-binding proteins; aggregation; gene mutations; nucleocytoplasmic transport.