C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

Yu Sun, Aziz Eshov, Jeffrey Zhou, Atagun U. Isiktas and Junjie U. Guo ()
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Yu Sun: Yale University School of Medicine
Aziz Eshov: Yale University School of Medicine
Jeffrey Zhou: Yale University School of Medicine
Atagun U. Isiktas: Yale University School of Medicine
Junjie U. Guo: Yale University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Expansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

Date: 2020
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DOI: 10.1038/s41467-020-17129-0

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