PARP1通路抑制分子RNF146调控星形胶质细胞凋亡在AD中的作用研究

项目名称： PARP1通路抑制分子RNF146调控星形胶质细胞凋亡在AD中的作用研究

项目编号： No.31460255

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 丁娟

作者单位： 宁夏医科大学

项目金额： 50万元

中文摘要： 脑组织β-淀粉样蛋白(Aβ)沉积是阿尔茨海默病(AD)重要的病理特征。传统认为Aβ沉积能够诱导神经元凋亡。最近发现Aβ沉积同样能够诱导星形胶质细胞（AS）凋亡。我们利用表达谱芯片筛选获得了在APP转基因小鼠大脑原代AS中表达下调的E3泛素连接酶RNF146，其能诱导聚腺苷二磷酸核糖聚合酶1（PARP1）泛素化降解，抑制PARP1介导的神经元死亡。我们发现：① Aβ能诱导原代AS中RNF146下调、PARP1水平增加以及细胞凋亡；②上调原代AS中RNF146表达，能改善Aβ诱导的AS凋亡。然而Aβ沉积是否是导致AS中RNF146下调的原因？RNF146下调促进AS凋亡的机制是什么？是否与PARP1的泛素化降解失调控有关？综上所述，我们将综合运用基因克隆、RNAi、病毒包装、电生理等方法，通过体内外实验,系统研究Aβ沉积对AS中RNF146表达和细胞凋亡的影响及调控机制，为AD防治提供新靶点。

中文关键词： RNF146；PARP1；凋亡；星形胶质细胞；阿尔茨海默病

英文摘要： Beta amyloid peptide (Aβ) deposition in brain tissue is one of the important pathological features in Alzheimer's disease (AD).Traditional view is that Aβ deposition can induce neuronal apoptosis. Recently, researchers have found that Aβ deposition can also induce astrocytes (AS) apoptosis. We screened the E3 ubiquitin ligase RNF146 expressed in the brain primary cultured AS of APP transgenic mice by the expression profile chip. RNF146 can induce poly (adp ribose polymerase 1 (PARP1) ubiquitin degradation, inhibit PARP1 mediated neural death. We found that: (1) Aβ could induce down-regulation of RNF146, increase levels of PARP1 and apoptosis in primary cultured AS; (2) Up-regulation of RNF146 can improve the apoptosis of AS induced by Aβ. However, whether Aβ deposition is the cause of RNF146 down-regulation in primary cultured AS or not? What is the mechanism of RNF146 down-regulation promote apoptosis of AS. Whether related to out of control of ubiquitin degradation of PARP1? In conclusion, we will comprehensively use methods of gene clone, RNAi, virus methods of packaging, electrophysiology, through experiments in vivo and in vitro, systematic research the effect and regulatory mechanism of RNF146 expression and cell apoptosis induced by Aβ deposition in AS. These will provide new targets for prevention and control of the AD.

英文关键词： RNF146;PARP1;Apoptosis;Astrocyte;Alzheimer's disease