HnRNP M expression rescues neurodegeneration in neuronal intranuclear inclusion disease mouse model by restoring dysregulated RNA splicing and transcription
Brief intro:
- Author: Yongcheng Pan, Yangping Li, Ying Jiang, Xinhui Wang, Juan Wan, Qiying Sun, Yun Tian, Lu Shen, Hong Jiang, Beisha Tang, Bing Yao, Qiong Liu
- Journal: Cell and Bioscience
- Doi: https://www.doi.org/10.1186/s13578-025-01477-9
- Publication Date: 2025/10/6
Abstract
Background: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by the expanded GGC repeats in the NOTCH2NLC gene, yet its underlying pathogenic mechanisms remains to be fully elucidated. Previous study suggests that hnRNP M, an RNA-binding protein sequestered into the inclusions, may contribute to RNA processing defects in NIID.
Results: In this study, we investigated the role of hnRNP M in NIID pathogenesis by utilizing a NOTCH2NLC-98GGC transgenic mouse model that faithfully recapitulates key NIID phenotypes. We found that AAV-mediated hnRNP M expression partially alleviated neuropathological features, such as neuronal loss and gliosis, and improved motor deficits in NIID mice. Transcriptome analysis further revealed that hnRNP M expression restored transcriptional and splicing dysregulation in synapse- and neurodegeneration-related genes, such as Dlg and Smn.
Conclusions: Our study established hnRNP M as a key regulator of NIID pathogenesis by modulating RNA transcription and splicing, underscoring the potential of targeting RNA processing abnormalities as a therapeutic strategy.
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