Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD. Issue 3 (11th December 2020)

• Record Type: Journal Article
• Authors: Odeh, Hana M.; Shorter, James
• Editors: Nott, Tim; Baldwin, Andrew
• Is Part Of: Emerging topics in life sciences. Volume 4:Issue 3(2020)
• Page Start: 293
• Page End: 305
• Publication Date: 2020-12-11
• Subjects: ALS -- dipeptide-repeat proteins -- FTD -- neurodegeneration -- phase separation -- RAN translation; Life sciences -- Periodicals; 570.5
• DOI: 10.1042/ETLS20190167
• Languages: English
• ISSNs: 2397-8554

Abstract

Abstract : A hexanucleotide repeat expansion GGGGCC (G4 C2 ) within chromosome 9 open reading frame 72 ( C9orf72 ) is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). This seminal realization has rapidly focused our attention to the non-canonical translation (RAN translation) of the repeat expansion, which yields dipeptide-repeat protein products (DPRs). The mechanisms by which DPRs might contribute to C9-ALS/FTD are widely studied. Arginine-rich DPRs (R-DPRs) are the most toxic of the five different DPRs produced in neurons, but how do R-DPRs promote C9-ALS/FTD pathogenesis? Proteomic analyses have uncovered potential pathways to explore. For example, the vast majority of the R-DPR interactome is comprised of disease-linked RNA-binding proteins (RBPs) with low-complexity domains (LCDs), strongly suggesting a link between R-DPRs and aberrations in liquid–liquid phase separation (LLPS). In this review, we showcase several potential mechanisms by which R-DPRs disrupt various phase-separated compartments to elicit deleterious neurodegeneration. We also discuss potential therapeutic strategies to counter R-DPR toxicity in C9-ALS/FTD.