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Background <p>Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by the expanded GGC repeats in the <i>NOTCH2NLC</i> 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.</p> Results <p>In this study, we investigated the role of hnRNP M in NIID pathogenesis by utilizing a <i>NOTCH2NLC-98GGC</i> 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 <i>Dlg</i> and <i>Smn</i>.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Yongcheng Pan,
  • Yangping Li,
  • Ying Jiang,
  • Xinhui Wang,
  • Juan Wan,
  • Qiying Sun,
  • Yun Tian,
  • Lu Shen,
  • Hong Jiang,
  • Beisha Tang,
  • Bing Yao,
  • Qiong Liu

摘要

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.