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

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.