HnRNP M expression rescues neurodegeneration in neuronal intranuclear inclusion disease mouse model by restoring dysregulated RNA splicing and transcription

作者：Yongcheng Pan, Yangping Li, Ying Jiang, Xinhui Wang, Juan Wan, Qiying Sun, Yun Tian, Lu Shen, Hong Jiang, Beisha Tang, Bing Yao, Qiong Liu · 发表于：Cell & Bioscience · 年份：2025 · DOI：10.1186/s13578-025-01477-9 · 被引用次数：2 · 研究领域：Genetic Neurodegenerative Diseases、RNA Research and Splicing、Neurogenetic and Muscular Disorders Research

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.