Functional rescue of a disease-linked ERAD pathway mutation via alternative splicing - PubMed
4 hours ago
- #Therapeutic Strategy
- #ERAD
- #Alternative Splicing
- ER-associated degradation (ERAD) targets misfolded proteins in the endoplasmic reticulum (ER) for proteasomal degradation.
- Mutations in the SEL1L-HRD1 complex cause ERAD-associated neurodevelopmental disorders (ENDI), with the most severe form being ENDI-A due to a SEL1L-Cys141Tyr mutation.
- Knock-in mouse models with the C141Y mutation were rescued via alternative splicing, bypassing the mutant region and restoring ERAD activity.
- Antisense oligonucleotide-mediated exon skipping in patient-derived fibroblasts generated a functional SEL1L protein, restoring ERAD function.
- RNA splicing-modulation is proposed as a therapeutic strategy for ERAD deficiency, expanding the potential of exon-skipping therapy to protein misfolding diseases.