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A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation

Author

Listed:
  • Yoshifumi Sonobe

    (University of Chicago Medical Center
    University of Chicago Medical Center
    University of Chicago)

  • Jihad Aburas

    (University of Chicago Medical Center
    University of Chicago
    University of Chicago)

  • Gopinath Krishnan

    (University of Massachusetts Medical School)

  • Andrew C. Fleming

    (Northwestern University)

  • Ghanashyam Ghadge

    (University of Chicago Medical Center
    University of Chicago Medical Center
    University of Chicago)

  • Priota Islam

    (MRC London Institute of Medical Sciences
    Imperial College London)

  • Eleanor C. Warren

    (MRC London Institute of Medical Sciences
    Imperial College London)

  • Yuanzheng Gu

    (Neuromuscular & Movement Disorders, Biogen)

  • Mark W. Kankel

    (Neuromuscular & Movement Disorders, Biogen)

  • André E. X. Brown

    (MRC London Institute of Medical Sciences
    Imperial College London)

  • Evangelos Kiskinis

    (Northwestern University)

  • Tania F. Gendron

    (Mayo Clinic)

  • Fen-Biao Gao

    (University of Massachusetts Medical School)

  • Raymond P. Roos

    (University of Chicago Medical Center
    University of Chicago Medical Center
    University of Chicago)

  • Paschalis Kratsios

    (University of Chicago Medical Center
    University of Chicago
    University of Chicago)

Abstract

A hexanucleotide repeat expansion GGGGCC in the non-coding region of C9orf72 is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxic dipeptide repeats (DPRs) are synthesized from GGGGCC via repeat-associated non-AUG (RAN) translation. Here, we develop C. elegans models that express, either ubiquitously or exclusively in neurons, 75 GGGGCC repeats flanked by intronic C9orf72 sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and poly-glycine-arginine [poly-GR]), display neurodegeneration, and exhibit locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats selectively reduces poly-GA steady-state levels and ameliorates disease, suggesting poly-GA is pathogenic. Importantly, loss-of-function mutations in the eukaryotic translation initiation factor 2D (eif-2D/eIF2D) reduce poly-GA and poly-GP levels, and increase lifespan in both C. elegans models. Our in vitro studies in mammalian cells yield similar results. Here, we show a conserved role for eif-2D/eIF2D in DPR expression.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26303-x
    DOI: 10.1038/s41467-021-26303-x
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    References listed on IDEAS

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