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- Title
A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation.
- Authors
Sonobe, Yoshifumi; Aburas, Jihad; Krishnan, Gopinath; Fleming, Andrew C.; Ghadge, Ghanashyam; Islam, Priota; Warren, Eleanor C.; Gu, Yuanzheng; Kankel, Mark W.; Brown, André E. X.; Kiskinis, Evangelos; Gendron, Tania F.; Gao, Fen-Biao; Roos, Raymond P.; Kratsios, Paschalis
- 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. A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Subjects
CAENORHABDITIS elegans; TRANSLATING &; interpreting; FRONTOTEMPORAL dementia; AMYOTROPHIC lateral sclerosis; MOTOR neuron diseases; PROTEIN expression; DEMENTIA patients
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-26303-x