Bibliographic Details
| 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 |
| Source: |
Nature Communications; 10/15/2021, Vol. 12 Issue 1, p1-17, 17p |
| Subject Terms: |
CAENORHABDITIS elegans, TRANSLATING & interpreting, FRONTOTEMPORAL dementia, AMYOTROPHIC lateral sclerosis, MOTOR neuron diseases, PROTEIN expression, DEMENTIA patients |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
