CK2磷酸化SET介导老年痴呆症Tau病理变化的机理研究

PP2A inactivation plays a pivotal role in abnormal tau phosphorylation and Alzheimer’s disease (AD) pathogenesis. Aberrant cytoplasmic localization of the nuclear protein SET is crucial for PP2A inactivation and tau pathological process, yet the mechanism is unknown. Meanwhile, Casein kinase (CK2), a known upstream protein kinase of SET, is highly expressed in AD brains. Previously we found that CK2 transfection causes an increase in SET phosphorylation at Ser9, SET cytoplasmic retention and a significant increase in PP2A activity. Current project aims at: 1. Detecting the phosphorylation and distribution of SET, PP2A activity, tau phosphorylation and neurodegeneration in CK2 transfected mice brain; studying behavioral changes in CK2 transfected mice with or without CK2 inhibitors; determining the effects of CK2 on SET phosphorylation in vivo; clarifying the molecular mechanism of CK2 induced tau pathology. 2. Detecting those indices listed in (1) after overexpression of phosphorylated SET in vitro and in vivo and illustrating on how SET phosphorylation leads to tau pathology. 3. Investigating whether mutation of SET’s Ser9 to Ala could rescue CK2 induced tau pathology and clarifying how CK2 mediated phosphorylation of SET induces tau pathology. The expected results will provide new clues to the AD pathogenesis and provide molecular drug targets for prevention and treatment.

PP2A失活致Tau异常磷酸化是AD关键事件。核蛋白SET滞留胞浆降低PP2A活性促发Tau病理变化，但SET异常分布的机制不明。同时，SET上游激酶CK2在AD脑内亦高表达。申请人发现：转染CK2后可见SET Ser9位点磷酸化并于胞浆聚集、PP2A活性显著下调。我们推测：CK2磷酸化SET影响其分布并通过抑制PP2A参与AD的Tau病变。本项目拟①检测有/无CK2抑制剂干预下CK2感染小鼠脑内SET磷酸化及分布、PP2A活性、Tau磷酸化、神经退变和行为学变化，探讨CK2在体对SET磷酸化修饰影响，明确上调CK2是否导致AD Tau病变；②过表达pSET，在细胞与整体水平检测①中内容，探明SET磷酸化引起Tau病变；③观测突变SET S9A是否阻断CK2引起的Tau病变，阐明CK2磷酸化SET Ser9介导Tau病变机制。本研究结果将为AD发病机制提供新线索，为其防治提供靶点。

蛋白磷酸酯酶2A（Protein phosphatase 2A， PP2A）失活致Tau异常磷酸化是阿尔茨海默病（Alzheimer disease, AD）关键事件。核蛋白SET滞留胞浆降低PP2A活性促发Tau病理变化，但SET异常分布的机制不明。同时，SET上游酪蛋白激酶2（Casein Kinase II, CK2）在tau及的神经元以及神经原纤维缠结的海马神经元中显著增加。然而，AD进程中，CK2是否磷酸化SET，并进而调控PP2A及tau磷酸化并参与AD发生未知。本项目研究了CK2磷酸化SET介导tau病变，进而促发神经纤维退变的具体分子机制。发现：1. 在AD模型鼠中证实CK2被激活并伴随着SET磷酸化；2. CK2磷酸化SET导致其滞留于胞浆；3. 过表达CK2引起小鼠学习记忆障碍；4. 磷酸化SET下调PP2A活性，促进tau的过度磷酸化；5. 过表达SET引发小鼠认知功能损伤；6. CK2通过磷酸化SET丝氨酸9位点介导tau病变。本研究成果为SET异常修饰参与AD发病机制提供了新线索，为AD药物开发提供有效特异的分子靶点。

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