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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations
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Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations

机译：早老素-1诱导Notch-1的蛋白水解释放和核易位，并受到致病性早老素-1突变的损害。

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摘要

The Notch family of proteins consists of transmembrane receptors that play a critical role in the determination of cell fate. Genetic studies in Caenorkabditis elegans suggest that the presenilin proteins, which are asso- ciated with familial Alzheimer's disease, regulate Notch sig- naling. Here we show that proteolytic release of the Notch-1 intracellular domain (NICD), an essential step in the activa- tion of Notch signaling, is markedly reduced in presenilin-1 (PS1)-deficient cells and is restored by PS1 expression. Nu- clear translocation of the NICD is also markedly reduced in PS1-deficient cells, resulting in reduced transcriptional acti- vation. Mutations in PS1 that are associated with familial Alzheimer's disease impair the ability of PS1 to induce proteolytic release of the NICD and nuclear translocation of the cleaved protein. These results suggest that PS1 plays a central role in the proteolytic activation of the Notch-1- signaling pathway and that this function is impaired by gathogenic PS1 mutations. Thus, dysregulation of proteolytic function may underlie the mechanism by which presenilin mutations cause Alzheimer's disease.
机译：Notch蛋白家族由跨膜受体组成，这些受体在决定细胞命运中起着至关重要的作用。秀丽隐杆线虫的遗传研究表明，早老蛋白与家族性阿尔茨海默氏病有关，可调节Notch信号。在这里，我们显示Notch-1细胞内域（NICD）的蛋白水解释放，这是Notch信号激活中的重要步骤，在早老素1（PS1）缺陷细胞中明显减少，并通过PS1表达得以恢复。在缺乏PS1的细胞中，NICD的核易位也显着减少，导致转录激活减少。与家族性阿尔茨海默氏病相关的PS1突变会削弱PS1诱导NICD的蛋白水解释放和裂解蛋白的核易位的能力。这些结果表明，PS1在Notch-1信号通路的蛋白水解激活中起着核心作用，而这种功能因致畸PS1突变而受损。因此，蛋白水解功能的失调可能是早老素突变引起阿尔茨海默氏病的机制的基础。

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