Protective role of PASH-1 in CGG repeat-driven RNA and protein toxicity in FXTAS - PubMed
a day ago
- #RNA toxicity
- #PASH-1
- #FXTAS
- FXTAS is caused by CGG repeat expansions in FMR1, leading to RNA toxicity and toxic FMRpolyG peptide production.
- A C. elegans model with human FMR1 5' UTR containing 99 CGG repeats showed impaired motility, altered neuronal morphology, and disrupted miRNA homeostasis.
- Co-expression of PASH-1, the C. elegans ortholog of DGCR8, mitigated RNA- and peptide-mediated toxicity, restoring locomotion, neuronal structure, and miRNA balance.
- Removing FMRpolyG improved movement by ~50%, indicating RNA toxicity as the primary pathogenesis.
- Glial 99 CGG expression altered nearby neuronal cilia, disrupting olfaction without affecting movement, revealing non-cell-autonomous toxicity.
- The study highlights PASH-1's protective role against CGG-induced neurotoxicity and validates C. elegans as a model for FXTAS research.