Kawamura Y, Kikuchi A, Takada R, Takada S, Sudoh S, Shibamoto S, Yanagisawa K, Komano H
Department of Dementia Research, National Insititute for Longevity Sciences, Obu, Aichi, Japan.
Eur J Biochem. 2001 May;268(10):3036-41. doi: 10.1046/j.1432-1327.2001.02197.x.
Mutations in the presenilin 1 (PS1) gene are the most common genetic factor underlying the development of early onset familial Alzheimer's disease (FAD). Accumulating evidence has shown that FAD-linked mutations of PS1 enhance the generation of amyloid-beta (1-42) protein. Recently, beta-catenin has been shown to interact with PS1. beta-catenin is essential for the Wnt signalling pathway. However, the biological significance of the interaction between beta-catenin and PS1 in this signalling pathway remains to be clarified. In this study, we investigated the effect of FAD-linked PS1 (M146L) mutation in the Wnt signalling pathway using the conditioned medium containing Wnt-3A. The expression of mutated PS1 inhibited the Wnt-3A-induced accumulation of beta-catenin. Chase analysis of beta-catenin in Wnt-3A-stimulated cells following cycloheximide treatment revealed that PS1 mutation enhanced the generation of the higher molecular mass form of beta-catenin, most likely, ubiquitinated beta-catenin. In addition, the expression of mutated PS1 elevated the level of phosphorylated beta-catenin, which is targeted to the ubiquitin/proteasome pathway. Thus, it appears that PS1 (M146L) mutation down-regulates the Wnt-3A-induced accumulation of beta-catenin due to an increase in the level of phosphorylated beta-catenin.
早老素1（PS1）基因突变是早发型家族性阿尔茨海默病（FAD）发生发展的最常见遗传因素。越来越多的证据表明，与FAD相关的PS1突变会增加β淀粉样蛋白（1-42）的生成。最近，β-连环蛋白已被证明与PS1相互作用。β-连环蛋白对Wnt信号通路至关重要。然而，β-连环蛋白与PS1在该信号通路中相互作用的生物学意义仍有待阐明。在本研究中，我们使用含有Wnt-3A的条件培养基研究了与FAD相关的PS1（M146L）突变在Wnt信号通路中的作用。突变型PS1的表达抑制了Wnt-3A诱导的β-连环蛋白积累。用放线菌酮处理Wnt-3A刺激的细胞后对β-连环蛋白进行追踪分析表明，PS1突变增强了高分子量形式的β-连环蛋白（很可能是泛素化的β-连环蛋白）的生成。此外，突变型PS1的表达提高了磷酸化β-连环蛋白的水平，而磷酸化β-连环蛋白是靶向泛素/蛋白酶体途径的。因此，由于磷酸化β-连环蛋白水平的增加，PS1（M146L）突变似乎下调了Wnt-3A诱导的β-连环蛋白积累。
