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C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation

Author

Listed:
  • Weiwei Cheng

    (Johns Hopkins University School of Medicine)

  • Shaopeng Wang

    (Johns Hopkins University School of Medicine)

  • Alexander A. Mestre

    (Johns Hopkins University School of Medicine)

  • Chenglai Fu

    (Johns Hopkins University School of Medicine)

  • Andres Makarem

    (Johns Hopkins University School of Medicine)

  • Fengfan Xian

    (Johns Hopkins University School of Medicine)

  • Lindsey R. Hayes

    (Johns Hopkins University School of Medicine)

  • Rodrigo Lopez-Gonzalez

    (University of Massachusetts Medical School)

  • Kevin Drenner

    (University of California at San Diego)

  • Jie Jiang

    (University of California at San Diego)

  • Don W. Cleveland

    (University of California at San Diego)

  • Shuying Sun

    (Johns Hopkins University School of Medicine)

Abstract

Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5′-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.

Suggested Citation

  • Weiwei Cheng & Shaopeng Wang & Alexander A. Mestre & Chenglai Fu & Andres Makarem & Fengfan Xian & Lindsey R. Hayes & Rodrigo Lopez-Gonzalez & Kevin Drenner & Jie Jiang & Don W. Cleveland & Shuying Su, 2018. "C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02495-z
    DOI: 10.1038/s41467-017-02495-z
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    Cited by:

    1. Malgorzata J. Latallo & Shaopeng Wang & Daoyuan Dong & Blake Nelson & Nathan M. Livingston & Rong Wu & Ning Zhao & Timothy J. Stasevich & Michael C. Bassik & Shuying Sun & Bin Wu, 2023. "Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Antonios Apostolopoulos & Naohiro Kawamoto & Siu Yu A. Chow & Hitomi Tsuiji & Yoshiho Ikeuchi & Yuichi Shichino & Shintaro Iwasaki, 2024. "dCas13-mediated translational repression for accurate gene silencing in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Yoshifumi Sonobe & Jihad Aburas & Gopinath Krishnan & Andrew C. Fleming & Ghanashyam Ghadge & Priota Islam & Eleanor C. Warren & Yuanzheng Gu & Mark W. Kankel & André E. X. Brown & Evangelos Kiskinis , 2021. "A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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