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

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, Tania F. Gendron, Fen-Biao Gao, Raymond P. Roos () and Paschalis Kratsios ()
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Yoshifumi Sonobe: University of Chicago Medical Center
Jihad Aburas: University of Chicago Medical Center
Gopinath Krishnan: University of Massachusetts Medical School
Andrew C. Fleming: Northwestern University
Ghanashyam Ghadge: University of Chicago Medical Center
Priota Islam: MRC London Institute of Medical Sciences
Eleanor C. Warren: MRC London Institute of Medical Sciences
Yuanzheng Gu: Neuromuscular & Movement Disorders, Biogen
Mark W. Kankel: Neuromuscular & Movement Disorders, Biogen
André E. X. Brown: MRC London Institute of Medical Sciences
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
Paschalis Kratsios: University of Chicago Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26303-x

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