Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases
Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases
复制标题
具有 NOTCH2NLC GGC 扩展的上游开放阅读框产生聚甘氨酸聚集体并破坏核细胞质运输：对聚甘氨酸疾病的影响。
DOI：
10.1007/s00401-021-02375-3
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发表时间：
2021-10-25
影响因子：
12.7
通讯作者：
Wang, Xin
中科院分区：
文献类型：
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作者：
Zhong, Shaoping;Lian, Yangye;Wang, Xin
神经元核内包涵体病（NIID）是以广泛分布的包涵体为特征的神经退行性疾病。尽管在成人型NIID中发现了NOTCH 2NLC基因5'UTR的GGC重复扩增，但其致病机制尚不清楚。非常规翻译产生的功能获得性多聚氨基酸蛋白在核苷酸重复序列扩增障碍中被发现，启发我们探索非常规翻译在NIID中的可能性。在这里，我们证明了NOTCH2NLC 5'UTR触发了含聚甘氨酸（polyG）的蛋白N2NLCpolyG的翻译。N2NLCpolyG在具有NOTCH 2NLC GGC扩增的培养细胞、小鼠模型和NIID患者组织中的p62阳性包涵体中积累。N2NLCpolyG的翻译由嵌入GGC重复序列的上游开放阅读框架（uORF）启动。N2NLCpolyG随着GGC重复单元的增加而趋于聚集，并显示相分离性质。N2NLCpolyG聚集损害核纤层和核质转运，但不一定导致神经元细胞的急性死亡。我们的研究表明NIID和另一种GGC重复疾病，脆性X相关震颤共济失调综合征之间的致病机制相似。这些发现扩展了我们对NIID中蛋白质功能获得的认识，并进一步强调了异常polyG蛋白聚集引起的一系列新疾病的证据，即polyG疾病。
Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disease characterized by widespread inclusions. Despite the identification of GGC repeat expansion in 5'UTR of NOTCH2NLC gene in adult-onset NIIDs, its pathogenic mechanism remains unclear. Gain-of-function poly-amino-acid proteins generated by unconventional translation have been revealed in nucleotide repeat expansion disorders, inspiring us to explore the possibility of unconventional translation in NIID. Here we demonstrated that NOTCH2NLC 5'UTR triggers the translation of a polyglycine (polyG)-containing protein, N2NLCpolyG. N2NLCpolyG accumulates in p62-positive inclusions in cultured cells, mouse models, and NIID patient tissues with NOTCH2NLC GGC expansion. Translation of N2NLCpolyG is initiated by an upstream open reading frame (uORF) embedding the GGC repeats. N2NLCpolyG tends to aggregate with the increase of GGC repeat units, and displays phase separation properties. N2NLCpolyG aggregation impairs nuclear lamina and nucleocytoplasmic transport but does not necessarily cause acute death on neuronal cells. Our study suggests a similarity of pathogenic mechanisms between NIID and another GGC-repeat disease, fragile X-associated tremor ataxia syndrome. These findings expand our knowledge of protein gain-of-function in NIID, and further highlight evidence for a novel spectrum of diseases caused by aberrant polyG protein aggregation, namely the polyG diseases.