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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.
Highlights
Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease that primarily targets motor neurons, is categorized into two forms, familial and sporadic
Genetic analyses of amyotrophic lateral sclerosis (ALS) patients have identified more than 100 ALS-related gene variants, including many genes encoding RNA-binding proteins (RBPs), such as transactivation response DNA-binding protein 43 (TDP-43), FUS, heterogeneous nuclear ribonucleoproteins A1, hnRNPA2/B1, matrin 3 (MATR3), ataxin 2 (ATXN2), TATA-box binding protein–associated factor 15 (TAF15), T-cell–restricted intracellular antigen 1 (TIA-1), and Ewing sarcoma breakpoint region 1 (EWSR1; Al-Chalabi et al, 2017; Nguyen et al, 2018)
TDP43 mutations are rare, TDP-43 proteinopathies, characterized by cytoplasmic mislocalization, aggregation, and cleavage of TDP-43 accompanied by its nuclear clearance, are found in the affected regions of the central nervous system (CNS) in up to 97% of all ALS cases, except for those Familiar ALS (fALS) caused by SOD1 or FUS mutations (Neumann et al, 2006; Mackenzie et al, 2010), suggesting a broader involvement for TDP-43 dysregulation in ALS
Summary
Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease that primarily targets motor neurons, is categorized into two forms, familial (genetically inherited) and sporadic (without apparent family history). Familiar ALS (fALS) is responsible for ∼5% to 10% of all ALS cases, whereas sporadic ALS (sALS) is the major form of the disease accounting for 90% to 95% of all cases (Brown and Al-Chalabi, 2017; van Es et al, 2017). As key regulators of RNA metabolism, RBPs play a vital role in maintaining the normal function of neuronal systems (Nussbacher et al, 2019). Under physiological conditions, these ALS-linked RBPs are involved in almost all aspects of RNA metabolism, including transcription, alternate splicing, mRNA transport, and stability. We highlight the emerging therapeutic intervention by targeting these ALS-implicated RBPs
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