Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease

神经退行性变 RNA剪接 发病机制 选择性拼接 生物 神经科学 转基因 转基因小鼠 包涵体 RNA结合蛋白 疾病 遗传学 细胞生物学 基因 核糖核酸 信使核糖核酸 病理 医学 免疫学 大肠杆菌
作者
Qiong Liu,Kailin Zhang,Yunhee Kang,Yangping Li,Penghui Deng,Yujing Li,Yun Tian,Qiying Sun,Yu Tang,Keqin Xu,Yao Zhou,Junling Wang,Jifeng Guo,Jia‐Da Li,Kun Xia,Qingtuan Meng,Emily G. Allen,Zhexing Wen,Ziyi Li,Hong Jiang,Lu Shen,Ranhui Duan,Bing Yao,Beisha Tang,Peng Jin,Yongcheng Pan
出处
期刊:Science Advances [American Association for the Advancement of Science]
卷期号:8 (47) 被引量:16
标识
DOI:10.1126/sciadv.add6391
摘要

GGC repeat expansions within NOTCH2NLC have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the NOTCH2NLC with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, an RNA binding protein known as alternative splicing regulator. Expanded NOTCH2NLC-polyG and NOTCH2NLC-polyA could interact with and sequester hnRNPM, while overexpression of hnRNPM could ameliorate the cellular toxicity. These results together suggested that dysfunction of hnRNPM could play an important role in the molecular pathogenesis of NIID.
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