Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.
Highlights
INTRODUCTIONSince the discovery of mutations in TARDBP, fused in sarcoma/translocated in liposarcoma (FUS), and C9ORF72 that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), numerous investigations have demonstrated the effect these mutations have on RNA metabolism, as well as how RNA itself contributes to pathogenicity (Tollervey et al, 2011; Xiao et al, 2011; Daigle et al, 2013; Donnelly et al, 2013; Gendron et al, 2013; Ihara et al, 2013; Lagier-Tourenne et al, 2013; Lee et al, 2013; Nakaya et al, 2013; Shodai et al, 2013; Cooper-Knock et al, 2014; Coyne et al, 2014, 2015, 2017a, 2020; Highley et al, 2014; Liu-Yesucevitz et al, 2014; Mackness et al, 2014; Barmada et al, 2015; Burguete et al, 2015; Tran et al, 2015; Conlon et al, 2016; Dodd et al, 2016; Garnier et al, 2017; Liu et al, 2017; Lu et al, 2017; Kamelgarn et al, 2018; Tank et al, 2018; Chen et al, 2019; Xu et al, 2019; Ortega et al, 2020; Sun et al, 2020; Zaepfel et al, 2021)
Normally compartmentalized within the nucleus, TDP-43 was first implicated in neurodegeneration when it was found that its presence in ubiquitin-positive cytoplasmic inclusions is a hallmark of sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Arai et al, 2006; Neumann et al, 2006)
Decades of research and independent investigations have provided clear evidence that RNA biology is commonly disrupted in the context of ALS
Summary
Since the discovery of mutations in TARDBP, FUS, and C9ORF72 that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), numerous investigations have demonstrated the effect these mutations have on RNA metabolism, as well as how RNA itself contributes to pathogenicity (Tollervey et al, 2011; Xiao et al, 2011; Daigle et al, 2013; Donnelly et al, 2013; Gendron et al, 2013; Ihara et al, 2013; Lagier-Tourenne et al, 2013; Lee et al, 2013; Nakaya et al, 2013; Shodai et al, 2013; Cooper-Knock et al, 2014; Coyne et al, 2014, 2015, 2017a, 2020; Highley et al, 2014; Liu-Yesucevitz et al, 2014; Mackness et al, 2014; Barmada et al, 2015; Burguete et al, 2015; Tran et al, 2015; Conlon et al, 2016; Dodd et al, 2016; Garnier et al, 2017; Liu et al, 2017; Lu et al, 2017; Kamelgarn et al, 2018; Tank et al, 2018; Chen et al, 2019; Xu et al, 2019; Ortega et al, 2020; Sun et al, 2020; Zaepfel et al, 2021). Mutations in all three of these genes have been linked to alterations in mRNA splicing and stress granule formation (Daigle et al, 2013; Nakaya et al, 2013; Conlon et al, 2016; Donde et al, 2019; Klim et al, 2019). We discuss a bulk of the findings where direct or indirect alterations in RNA-related pathways have been linked to mutations in these three genes. We address the role of RNA itself in mediating this toxicity. With a focus on the structure of proteins as they relate to RNA-binding. RNA Toxicity in ALS and -processing functions, we provide new insight into the bi-directional effect between RNA itself and altered RNA processing in ALS
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