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Significance Amyotrophic laterosclerosis (ALS) is a rapidly progressing neurological disease that robs patients’ motor functions. Despite intensive research, molecular events that initiate the disease are poorly understood. Expansion of G4C2 repeats in theC9orf72 gene causes ALS with frontotemporal dementia, one of the most common forms of ALS. Increasing evidence suggests that dipeptides translated from G4C2 repeat transcripts, especially the arginine-containing poly(GR) and poly(PR), are particularly toxic. We found that translation of poly(GR) can occur on mitochondrial surface and is frequently stalled, triggering ribosome-associated quality control and C-terminal extension, which promote poly(GR) aggregation and toxicity. Genetic studies uncovered conserved roles of mitochondrial protease YME1L and noncanonical Notch signaling in restraining poly(GR), offering insights into disease pathogenesis and targets for therapeutic intervention.

Quality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD