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

Nat Commun. 2021 Oct 15;12(1):6025. doi: 10.1038/s41467-021-26303-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Arginine
  • C9orf72 Protein / genetics*
  • Caenorhabditis elegans / genetics*
  • Dipeptides / metabolism
  • Female
  • Frontotemporal Dementia / genetics*
  • Gene Editing
  • Gene Knockdown Techniques
  • Glycine
  • HEK293 Cells
  • Humans
  • Middle Aged
  • Motor Neurons
  • Nerve Degeneration
  • Proline


  • C9orf72 Protein
  • Dipeptides
  • Arginine
  • Proline
  • Alanine
  • Glycine

Supplementary concepts

  • Frontotemporal Dementia With Motor Neuron Disease