Project description:GGC repeat expansion within NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here we have established both a transgenic mouse model and a human neural progenitor cell (hNPC) model. We show that the expression of the NOTCH2NLC gene with expanded GGC repeats produces multiple forms of polypeptides, including polyglycine (polyG), polyalanine (polyA) and polyarginine (polyR), and leads to widespread intranuclear inclusions, severe neurodegeneration, motor dysfunction and cognitive deficits, which faithfully mimics the clinical manifestations and pathological features associated with NIID. We further performed RNA-seq on the prefrontal cortex, cerebellum and hippocampus of the transgenic mice and on the hNPC model and identified a large proportion of conserved alternative splicing between the NIID mouse and hNPC cell models. Analyses of the conserved alternative splicing revealed the enrichment of the binding motif of hnRNPM. We found that hnRNPM could interact with and be sequestered by expanded NOTCH2NLC-polyG and -polyA. Functional expression of hnRNPM could ameliorate the cellular toxicity caused by expanded GGC repeats within NOTCH2NLC. These results together suggest that dysregulated alternative splicing could play a vital role in the molecular pathogenesis of NIID.

2023-01-04 | GSE182878 | GEO

NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson's disease-like phenotypes in mice.

Project description: Not available

| S-EPMC11603791 | biostudies-literature

Adult-Onset Alcohol Suppressible Cervical Dystonia: A Case Report.

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| S-EPMC6183003 | biostudies-literature

Mutations in CIZ1 cause adult onset primary cervical dystonia.

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| S-EPMC3334472 | biostudies-literature

Is Routine Neuroimaging Needed in Adult-Onset Isolated Cervical Dystonia?

Project description: Not available