靶向活化SIRT1调节tau外显子10可变剪接在阿尔茨海默病防治中的作用

项目名称： 靶向活化SIRT1调节tau外显子10可变剪接在阿尔茨海默病防治中的作用

项目编号： No.81473218

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 钱慰

作者单位： 南通大学

项目金额： 70万元

中文摘要： Tau的病变导致神经退行性疾病，称tau蛋白病。经可变剪接，正常人脑表达六种tau变异体。外显子10是否编码决定tau含3或4个微管结合重复片段(3R、4R)，正常人脑中比例约为1。Tau mRNA异常剪接使其表达失衡，引起某些tau蛋白病。SC35是调节tau外显子10可变剪接的重要剪接因子，活性受磷酸化严格调节，而乙酰化对其功能调控的研究薄弱。SIRT1是与AD相关的去乙酰化酶。预实验发现1.SIRT1调节外显子10可变剪接；2.SIRT1抑制SC35所促进的外显子10的编码；3.SIRT1与SC35相互作用；4.AD患者脑中3R/4R-tau表达失衡，SIRT1表达下降。提示SIRT1与AD患者脑中tau外显子10剪接失调有关。本课题拟在分子、细胞、动物和AD患者脑组织，系统研究靶向调节SIRT1对外显子10可变剪接的影响，为与tau外显子10剪接相关神经退行性疾病的防治提供分子依据

中文关键词： Tau蛋白；SIRT1；白藜芦醇；SC35；可变剪接

英文摘要： Tau malfunction can trigger neurodegeneration, known as tauopathies. Adult human brain expresses six isoforms of tau from a single gene by alternative splicing of its pre-mRNA. Alternative splicing of exon 10 (E10) divides tau isoforms into two main groups, three (3R)- or four (4R)-microtubule-binding repeat tau. Approximately equal amounts of 3R-tau and 4R-tau are expressed in normal adult human brain. Imbalance of 4R-tau/3R-tau results in tauopathies. Splicing factor SC35 play very important role in the promotion of tau exon 10 inclusion. It's activity is highly regulated by phosphorylation. But the function of another post-translational modification of SR proteins known as acetylation has not been determined. In the preliminary data, we found that: 1. SIRT1 regulated the alternative splicing of tau exon 10; 2. the promotion of tau exon 10 inclusion by SC35 was markedly suppressed by overexpressed SIRT1; 3. SIRT1 directly interacted with SC35; 4. in AD brain, the balance of 3R tau and 4R tau was disrupted and the protein level of SIRT1 was decreased. These data indicate that the reduction of SIRT1 may correlate with the dysregulation of tau exon 10 splicing in AD brain. The specific goal of this project is to investigate how the targeted adjustment of SIRT1 regulates the alternative splicing of tau exon 10 in vitro and in vivo even in AD brain, which will provide significant new insights into the molecular mechanism of neurodegenerative disease related to the alternative splicing of tau exon 10.

英文关键词： tau;SIRT1;resveratrol;SC35;alternative splicing