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

• DOI: 10.1073/pnas.2005506117
• Publication Date: 2020-09-22T00:41:25Z
• Authors: Shuangxi Li; Zhihao Wu; Ishaq Tantray; Yu Li; Songjie Chen; Jason Dong; Steven Glynn; Hannes Vogel; Michael Snyder; Bingwei Lu
• Keywords: 0301 basic medicine; DNA Repeat Expansion; C9orf72 Protein; Proteome; Receptors, Notch; Amyotrophic Lateral Sclerosis; Metalloendopeptidases; Arginine; Mitochondria; Mitochondrial Proteins; Disease Models, Animal; 03 medical and health sciences; Drosophila melanogaster; HEK293 Cells; Frontotemporal Dementia; Protein Biosynthesis; ATPases Associated with Diverse Cellular Activities; Animals; Drosophila Proteins; Humans; Ribosomes; Signal Transduction

SignificanceAmyotrophic 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 theC9orf72gene 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.