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A Second Pathogenic Protein, PolyGN2C-iso2, Reveals a Dual-Protein Pathology in Neuronal Intranuclear Inclusion
Kang Zhang1, Wenhao Ma2,3,4, Yi Zhou1
1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 23, 2026
Summary
Neuronal intranuclear inclusion disease (NIID) involves two pathogenic proteins, uN2CpolyG and PolyGN2C-iso2, originating from NOTCH2NLC transcripts. This discovery offers new therapeutic targets for NIID.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neuronal intranuclear inclusion disease (NIID) pathogenesis is linked to uN2CpolyG from NOTCH2NLC transcript variant 1.
- Evidence suggests NOTCH2NLC transcript variant 2 also generates a disease-relevant protein, PolyGN2C-iso2, but requires further validation.
Purpose of the Study:
- To investigate the pathogenic role of PolyGN2C-iso2 in NIID.
- To develop tools for detecting PolyGN2C-iso2 and validate its presence in patient tissues.
- To establish and characterize a mouse model for PolyGN2C-iso2-induced NIID.
Main Methods:
- In vitro characterization of PolyGN2C-iso2 aggregation.
- Development of isoform-discriminating antibodies for PolyGN2C-iso2 detection.
- Targeted proteomics on patient tissues and laser-microdissected cells.
- Generation and analysis of an AAV-mediated mouse model expressing PolyG(108×)N2C-iso2.
Main Results:
- PolyGN2C-iso2 aggregates in vitro and is detected in NIID patient intranuclear inclusions, co-localizing with uN2CpolyG.
- The PolyG(108×)N2C-iso2 mouse model exhibits NIID hallmarks, including white matter abnormalities and cognitive deficits.
- PolyGN2C-iso2 expression induces significant mitochondrial dysfunction.
Conclusions:
- NIID pathogenesis may involve a dual-protein mechanism with both uN2CpolyG and PolyGN2C-iso2.
- These findings have implications for developing novel therapeutic strategies targeting NOTCH2NLC-derived proteins in NIID.
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