PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila
PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila
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DOI：
10.1016/s0092-8674(04)00170-9
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发表时间：
2004-03-05
期刊：
影响因子：
64.5
通讯作者：
Lu, BW
中科院分区：
文献类型：
--
作者：
Nishimura, I;Yang, YF;Lu, BW
Tau的多位点过度磷酸化参与了包括阿尔茨海默病(AD)在内的神经退行性疾病的发病机制。然而，对tau毒性至关重要的磷酸化事件以及调节这些事件的机制在很大程度上是未知的。在这里，我们证明了果蝇PAR-1激酶通过触发时间有序的磷酸化过程来启动tau毒性。PAR-1在S262和S356直接磷酸化tau。这种磷酸化事件是下游激酶，包括糖原合成酶激酶3(GSK-3)和细胞周期蛋白依赖性激酶-5(CDK5)磷酸化其他几个位点并产生疾病相关磷酸表位的先决条件。PAR-1磷酸化位点的突变比突变S202引起的tau磷酸化和毒性的降低要大得多，这进一步强调了PAR-1的启动子作用。S202是下游位点之一，其磷酸化依赖于先前的PAR-1作用。这些发现开始区分不同的磷酸化事件对tau毒性的影响，并提供潜在的治疗靶点。
Multisite hyperphosphorylation of tau has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). However, the phosphorylation events critical for tau toxicity and mechanisms regulating these events are largely unknown. Here we show that Drosophila PAR-1 kinase initiates tau toxicity by triggering a temporally ordered phosphorylation process. PAR-1 directly phosphorylates tau at S262 and S356. This phosphorylation event is a prerequisite for the action of downstream kinases, including glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase-5 (Cdk5), to phosphorylate several other sites and generate disease-associated phospho-epitopes. The initiator role of PAR-1 is further underscored by the fact that mutating PAR-1 phosphorylation sites causes a much greater reduction of overall tau phosphorylation and toxicity than mutating S202, one of the downstream sites whose phosphorylation depends on prior PAR-1 action. These findings begin to differentiate the effects of various phosphorylation events on tau toxicity and provide potential therapeutic targets.