EFFECT OF PRESENILIN 1 FAD-LINKED MUTATIONS ON BETA-CATE

阿尔茨海默病的两个主要特征是-淀粉样蛋白沉积和神经元细胞死亡。大约一半的早发性家族性阿尔茨海默病是由早老素基因PS1和PS2的突变引起的。fad相关的早老素突变是导致Abeta40: Abeta42比值升高和细胞凋亡易感性增加的原因。为了阐明早老素的生物学功能，已经努力鉴定与早老素相互作用的分子。我们最近发现，在H4神经胶质瘤细胞中，PS1的内源性c端片段（PS1 -CTF）与内源性β -连环蛋白相互作用，我们在这里报道gsk3 β也在同一复合物中被招募。由于gsk3 β负责β -连环蛋白的磷酸化和降解，因此β -连环蛋白/ gsk3 β /PS1复合物可能参与了游离β -连环蛋白水平的调控，而游离β -连环蛋白是β -连环蛋白信号传导的限制因子。迄今为止，已经报道了PS1 fad相关突变对β -连环蛋白水平调控的相反作用。PS1 fad相关突变对PS1/ gsk3 β结合的矛盾效应也有报道：PS1 gsk3 β结合增加或gsk3 β募集缺陷。本研究的目标是进一步研究PS1 fad相关突变对GKS3beta活性和β -连环蛋白调控的作用。gsk3 β / β -连环蛋白通路改变的鉴定将是未来研究（RO1）的基础，旨在研究这种改变如何影响阿尔茨海默病中β的产生和/或神经元细胞死亡。

The two major hallmarks of Alzheimer's disease are beta-amyloid deposition and neuronal cell death. Roughly half of early-onset familial Alzheimer's disease is caused by mutations in the presenilin genes, PS1 and PS2. FAD-linked presenilin mutations are responsible for both the production of an elevated ratio Abeta40: Abeta42 and an increased susceptibility to apoptosis. To elucidate the biological function of presenilins, efforts have been made to identify molecules that interact with presenilins. We have recently found that the endogenous C-terminal fragment of PS1 (PS1 -CTF) interacts with endogenous beta-catenin in H4 neuroglioma cells and we report here that GSK3beta is also recruited in the same complex. Since GSK3beta is responsible for beta-catenin phosphorylation and degradation, it is possible that beta-catenin/GSK3beta/PS1 complex might be involved in the regulation of free beta-catenin level that is a limiting factor for beta-catenin signaling. To date, opposite effects of PS1 FAD-linked mutations have been reported on the regulation of beta-catenin level. Contradictory effect of PS1 FAD-linked mutations have been also reported for PS1/GSK3beta binding: increased PS1 GSK3beta binding or defect of GSK3beta recruitment. The goal of the present proposal is to further investigate the role of PS1 FAD-linked mutations on GKS3beta activity and beta-catenin regulation. The identifications of alterations in GSK3beta/beta-catenin pathway will be the basis for a future research projected (RO1) aimed to study how such alterations may affect Abeta production and/or neuronal cell death in Alzheimer's disease.