A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration
A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration
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DOI：
10.1093/hmg/ddq068
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Iijima, Koichi
中科院分区：
文献类型：
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作者：
Iijima-Ando, Kanae;Zhao, LiJuan;Iijima, Koichi
微管相关蛋白tau的过度磷酸化在包括阿尔茨海默病(AD)在内的一系列神经退行性疾病患者的大脑中被检测到。在疾病相关部位，tau的磷酸化和/或去磷酸化的失衡被认为启动了tau在疾病发病机制中的异常代谢和毒性。然而，在AD中tau异常磷酸化的机制还不完全清楚。在这里，我们证明了DNA损伤激活的检查点激酶2(Chk2)是一种新的tau激酶，并在转基因果蝇模型中增强了tau的毒性。在表达人tau的转基因果蝇中，过度表达果蝇Chk2增加了tau在Ser262位的磷酸化，并加强了tau诱导的神经变性。非磷酸化的Ser262Ala突变可阻断Chk2诱导的tau毒性增强，提示Ser262磷酸化位点参与了Chk2对tau毒性的增强。体外激酶分析表明，人Chk2和一个密切相关的检查点激酶1(Chk1)直接磷酸化Ser262处的人tau。我们还证明了果蝇Chk2不调节果蝇微管亲和力调节激酶同系物的活性，该微管亲和力调节激酶已被证明是一种生理tau Ser262激酶。由于在AD患者脑组织中检测到DNA损伤的积累，我们的结果提示DNA损伤激活的激酶Chk1和Chk2可能参与了tau的磷酸化和毒性在AD的发病机制中的作用。
Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD.