期刊
EMERGING TOPICS IN LIFE SCIENCES
卷 4, 期 3, 页码 293-305出版社
PORTLAND PRESS LTD
DOI: 10.1042/ETLS20190167
关键词
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资金
- AstraZeneca
- Target ALS
- ALS Association
- Robert Packard Center for ALS Research
- G. Harold and Leila Y. Mathers Foundation
- Life Extension Foundation
- Sanofi
- Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-17-1-0237]
- NIH [R01GM099836, R21NS090205, R21AG065854]
A hexanucleotide repeat expansion GGGGCC (G(4)C(2)) 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.
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