Tau的SUMO化修饰是阿尔兹海默氏病的发病机制吗？

Alzheimer's disease (AD) is the most comment neurodegenerative disorder in the elderly and often result in memory loss and progressive cognitive impairment. Extracellular senile plaques deposits formed by β-amyloid (Aβ) accumulation and intracellular neurofibrillary tangles (NFTs) consisted of hyperphosphorylated tau (p-tau) are the major pathogenesis and the most prominent pathological hallmarks of AD. Tau hyperphosphorylation can increase SUMOylation of tau and inhibit p-tau degradation by ubiquitin. . SUMO is the small ubiquitin-like modify protein in human and competes substrate with ubiquitin. Tau SUMOylation might regulate stability of tau in AD. However, in the present study, little is known about the sure mechanism why hyperphosphorylated tau degradation inhibits in AD.. In our study we prepare to simulate tau hyperphosphorylation model in HEK293 cells transfected tau plasmids and observe the interaction of tau hyperphosphorylation, tau SUMOylation and tau ubiquitylation. Meanwhile, we research the above same correlation when SUMO over-express and inhibit. We still study the interrelation of tau hyperphosphorylation, tau SUMOylation and tau ubiquitylation by using the same methods in animal level. These data might demonstrate the hypothesis that p-tau SUMOylation inhibits its degradation by competing p-tau ubiquitylation and results in the effect of accumulating the p-tau. These might be a new clues of AD pathogenesis.

阿尔茨海默病（AD），是常见的神经退行性疾病，常导致记忆力减退和进行性认知功能障碍，主要发病机制为Aβ聚集导致老年斑和tau 蛋白异常过度磷酸化导致神经原纤维缠结。tau异常过度磷酸化后可增强其SUMO化修饰，同时不能被泛素降解。.SUMO为人体内小泛素样修饰分子，可与泛素竞争底物。在AD中修饰tau调节其稳定性。目前研究尚未见AD中磷酸化tau为什么不能被降解的明确机制。.本项目拟在HEK293细胞中转染tau并模拟tau异常过度磷酸化，运用免疫共沉淀、免疫荧光等方法，探讨tau磷酸化与其SUMO化、泛素化相关性；探索tau的SUMO化过表达和抑制时三者关系。运用同样的思路在整体水平探索tau磷酸化与其SUMO化、泛素化的相关性以及tau的SUMO化过表达和抑制时三者关系，验证磷酸化的tau使其SUMO化抑制了其泛素化修饰，导致磷酸化的tau不能被降解的假说，为AD发病机制提供新线索。

SUMO为人体内小泛素样修饰分子，可与泛素竞争底物。在阿尔兹海默病（Alzheimer’s disease, AD）中修饰tau调节其稳定性。tau异常过度磷酸化后可增强其SUMO化修饰，同时不能被泛素降解。本项目通过免疫共沉淀、免疫印迹、免疫荧光等技术在HEK293细胞中探讨了tau磷酸化与其SUMO化、泛素化相关性；探索tau的SUMO化过表达和抑制时三者关系。运用同样的思路在和AD模型大鼠中探索tau磷酸化与其SUMO化、泛素化的相关性以及tau的SUMO化过表达和抑制时三者关系，验证磷酸化的tau使其SUMO化抑制了其泛素化修饰，导致磷酸化的tau不能被降解的假说，为AD发病机制提供了新线索。同时在体水平使用SUMO-1抑制剂Ginkgolic Acid海马定位注射探索其对tau蛋白磷酸化影响及AD大鼠认知功能影响正在进行。同期还开展了临床上运用石杉碱甲治疗阿尔兹海默病观察其对认知功能障碍的疗效工作并已完成。综合上述结果，本研究为探讨tau的磷酸化和SUMO化之间的关系以及促进其磷酸化及抑制降解提高了重要的启示性线索。项目资助发表论文四篇，待发表四篇，根据实验结果撰写的一篇论文获湖北省第十六届自然科学优秀学术论文二等奖。培养研究生3名，其中1名已经取得硕士学位，2名在读。项目投入经费49万元，支出377,930.00元，各项支出基本与预算相符。剩余经费112,070.00元，剩余经费计划用于本项目研究后续支出。

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