Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis
Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis
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DOI：
10.1038/27208
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发表时间：
1998-10-15
期刊：
影响因子：
64.8
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Zhang, ZH;Hartmann, H;Yankner, BA
早老素-1基因突变是家族性早发性阿尔茨海默病的主要原因(1-4)。早老素-1可以与连环蛋白信号蛋白家族的成员联系在一起，但这种联系的意义尚不清楚(5，6)。在这里，我们发现早老素-1在体内与β-连环素形成复合体，增加了β-连环素的稳定性，早老素-1基因的致病突变降低了早老素-1稳定β-连环素的能力，并导致转基因小鼠大脑中β-连环素的降解增加，此外，早老素-1突变的阿尔茨海默病患者的大脑中β-连环素水平显著降低。β-连环蛋白信号的缺失增加了神经元对淀粉样β蛋白诱导的细胞凋亡的易感性，因此，早老素-1的突变可能通过改变β-连环蛋白的稳定性而增加神经元的凋亡，从而使个体容易患上早发性阿尔茨海默病。
Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease(1-4). Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown(5,6). Here we show that presenilin-1 forms a complex with beta-catenin in vivo that increases beta-catenin stability, Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize beta-catenin, and lead to increased degradation of beta-catenin in the brains of transgenic mice, Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-beta protein, Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer's disease.