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

• DOI: 10.1038/s41467-021-26303-x
• Publication Date: 2021-10-15T15:30:38Z
• Authors: 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; Paschalis Kratsios
• Keywords: C9ORF72

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