Glycogen Synthase Kinase-3β and Tau Genes Interact in Alzheimer's Disease
Glycogen Synthase Kinase-3β and Tau Genes Interact in Alzheimer's Disease
复制标题
DOI：
10.1002/ana.21476
复制
发表时间：
2008-10-01
影响因子：
11.2
通讯作者：
Schofield, Peter R.
中科院分区：
文献类型：
--
作者：
Kwok, John B. J.;Loy, Clement T.;Schofield, Peter R.
目的：我们检测了糖原合酶激酶3β（GSK3B）基因和微管相关蛋白Tau（MAPT）基因单倍型在阿尔茨海默病（AD）中的上位效应。方法：对三个AD队列进行了遗传关联研究。使用线性回归分析来检查 MAPT 多态性对基因表达和选择性剪接的影响。在用 GSK3B 和 MAPT 互补 DNA 组合转染的细胞中，使用蛋白质印迹和荧光素酶报告基因测定法测定 β-连环蛋白水平和信号传导。结果：在三个迟发性 AD 队列中观察到 GSK3B 和 MAPT 基因之间一致的相互作用，其中 GSK3B 单倍型 (T-T) 显着增加至少具有一种 H2 单倍型的个体患 AD 的风险 （优势比，1.68-2.33；p = 0.005-0.036）。在调整年龄和性别的影响后，GSK3B 单倍型在中国队列中具有显着的保护性（比值比，0.33；p = 0.016）。通过测量小脑转录本确定，两种 MAPT 单倍型（H1 和 H2）之间的体内转录效率存在显着差异（p < 0.001）。与对照载体相比，MAPT 或 GSK3B 的过度表达导致 β-连环蛋白水平降低 (p < 0.001)。相反，这两种分子的共转染增加了 β-连环蛋白信号传导。解释：我们的遗传和生化分析已经确定了 Tau 和 GSK-3 β 在迟发性 AD 致病因素中的新相互作用。我们的数据与相互作用的上位模型一致，其中 GSK3B 和 MAPT 基因表达水平不一致可能导致 β-连环蛋白水平和致病性改变。
Objective: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3 beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD).Methods: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA.Results: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling.Interpretation: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3 beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.