A hexanucleotide repeat expansion GGGGCC (G4C2) 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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December 2020
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Arginine-rich dipeptide repeat proteins (R-DPRs) disrupt various phase-separated compartments in neurodegenerative disease. In this special Phase Transitions issue of Emerging Topics in Life Sciences, Odeh and Shorter discuss the therapeutic strategies utilised to combat the deleterious effects of R-DPRs. These include the use of small molecule inhibitors, antisense oligonucleotides (ASOs), antibody immunotherapy (anti-DPRs), and “bait” RNAs. Find out more on pages 293–305.
Review Article|
July 08 2020
Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD
Hana M. Odeh;
Hana M. Odeh
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
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James Shorter
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
Correspondence: James Shorter ([email protected])
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Publisher: Portland Press Ltd
Received:
May 15 2020
Revision Received:
June 15 2020
Accepted:
June 17 2020
Online ISSN: 2397-8562
Print ISSN: 2397-8554
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology
2020
Emerg Top Life Sci (2020) 4 (3): 293–305.
Article history
Received:
May 15 2020
Revision Received:
June 15 2020
Accepted:
June 17 2020
Citation
Hana M. Odeh, James Shorter; Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD. Emerg Top Life Sci 11 December 2020; 4 (3): 293–305. doi: https://doi.org/10.1042/ETLS20190167
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