ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence

Apr 6, 2026Nature communications

ASO therapy may reverse DNA damage, 3D genome structure problems, and cell aging caused by NOTCH2NLC GGC repeat expansion

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Abstract

PolyG aggregates in neuronal intranuclear inclusion disease disrupt ribosomal homeostasis and impair chromatin organization.

Abnormal GGC repeat expansion in the NOTCH2NLC gene leads to the formation of polyG aggregates.
These aggregates mislocalize nucleophosmin and downregulate fibrillarin, affecting cellular functions.
PolyG aggregates interact with nucleophosmin and rRNA, resulting in disrupted ribosomal homeostasis.
Downregulation of chromatin structural proteins CTCF and RAD21 is associated with impaired chromatin organization.
Brain organoids from patients exhibit nucleolar stress and genome-wide chromatin structural alterations, linked to increased DNA damage and cellular aging.
Antisense oligonucleotides targeting GGC may reduce polyG aggregation and improve related molecular defects.

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Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis. Furthermore, polyG facilitates the downregulation of chromatin structural proteins CTCF and RAD21, thereby impairing chromatin organization. This pathological manifestation can be mitigated by restoring CTCF/RAD21 expression. Furthermore, in brain organoids derived from neuronal intranuclear inclusion disease patients, we observe nucleolar stress accompanied by genome-wide chromatin structural alterations. These changes correlate with increased DNA damage and cellular senescence phenotypes. Notably, antisense oligonucleotides targeting GGC effectively reduce polyG aggregation and ameliorate related molecular defects, ultimately alleviating senescence-associated phenotypes. These findings establish key mechanisms underlying neuronal intranuclear inclusion disease pathogenesis and provide proof-of-concept for targeted therapy.

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ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence

Abstract

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