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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.

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