Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds - PubMed
6 hours ago
- #ALS/FTD
- #Protein Aggregation
- #RNA Scaffolds
- Biomolecular condensates are important in health and disease, with pathogenic mechanisms not fully understood.
- In c9ALS/FTD caused by C9orf72 GGGGCC repeats, expanded RNA and poly(GR) products are key pathogenic factors.
- GGGGCC-repeat RNA and poly(GR) form cocondensates in vitro and in cells.
- RNA structures (G-quadruplex and hairpin) act as scaffolds to accelerate poly(GR) aggregation from liquid to solid phases.
- Hairpin structures promote amorphous solid-like condensates and reduce poly(GR) mobility.
- Cocondensation exacerbates nucleolar stress and cellular toxicity.
- Targeting RNA structures with small molecules reduces poly(GR) aggregation and improves cellular dysfunction.
- Findings emphasize RNA's role in regulating protein aggregation and suggest new therapeutic targets for pathogenic condensates.