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

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  • Yu Sun

    (Yale University School of Medicine
    Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine)

  • Aziz Eshov

    (Yale University School of Medicine
    Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine)

  • Jeffrey Zhou

    (Yale University School of Medicine
    Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine)

  • Atagun U. Isiktas

    (Yale University School of Medicine
    Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine)

  • Junjie U. Guo

    (Yale University School of Medicine
    Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine)

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.

Suggested Citation

  • Yu Sun & Aziz Eshov & Jeffrey Zhou & Atagun U. Isiktas & Junjie U. Guo, 2020. "C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17129-0
    DOI: 10.1038/s41467-020-17129-0
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    Cited by:

    1. Hyun Jung Hwang & Tae Lim Park & Hyeong-In Kim & Yeonkyoung Park & Geunhee Kim & Chiyeol Song & Won-Ki Cho & Yoon Ki Kim, 2023. "YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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