ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence - PubMed
3 hours ago
- #Neuronal intranuclear inclusion disease
- #Antisense oligonucleotide therapy
- #Chromatin organization
- ASO therapy reduces polyG protein aggregation and alleviates senescence-related defects in neuronal intranuclear inclusion disease models.
- Expanded GGC repeats in NOTCH2NLC produce polyG protein that aggregates, causing nucleophosmin mislocalization and fibrillarin downregulation, disrupting ribosomal homeostasis.
- PolyG aggregates contribute to the downregulation of chromatin structural proteins CTCF and RAD21, leading to impaired chromatin organization and genome-wide structural changes.
- Pathological changes include increased DNA damage and cellular senescence, which are rescued by restoring CTCF/RAD21 expression or using GGC-targeting antisense oligonucleotides.
- The findings establish mechanisms of disease pathogenesis and provide a proof-of-concept for targeted therapy using antisense oligonucleotides.