Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy
Ca2+/calmodulin-dependent protein kinase II promotes neurodegeneration caused by tau phosphorylated at Ser262/356 in a transgenic Drosophila model of tauopathy
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DOI：
10.1093/jb/mvx038
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发表时间：
2017-11
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影响因子：
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通讯作者：
Mikiko Oka;Naoki Fujisaki;Akiko Maruko-Otake;Y. Ohtake;Sawako Shimizu;Taro Saito;S. Hisanaga;Koichi M. Iijima;K. Ando
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文献类型：
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作者：
Mikiko Oka;Naoki Fujisaki;Akiko Maruko-Otake;Y. Ohtake;Sawako Shimizu;Taro Saito;S. Hisanaga;Koichi M. Iijima;K. Ando
微管相关蛋白tau的异常沉积是包括阿尔茨海默病（AD）在内的多种神经退行性疾病的共同病理特征，并且在其发病机制中起关键作用。钙稳态和下游激酶Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）的破坏与AD脑中tau蛋白的病理性磷酸化一致。然而，目前尚不清楚CaMKII的失调是否以及如何影响tau毒性。使用果蝇模型，我们发现CaMKII促进由AD相关位点Ser 262/356处的tau磷酸化引起的神经变性。过表达的CaMKII促进，而RNA介导的敲低CaMKII和抑制CaMKII活性的抑制肽的表达抑制，tau介导的神经变性。通过丙氨酸取代阻断Ser 262/356处的tau磷酸化抑制了CaMKII对tau毒性的促进作用，表明这些位点处的tau磷酸化是这种现象所必需的。然而，无论是敲低还是过表达的CaMKII影响tau蛋白在Ser 262/356的磷酸化水平，这表明CaMKII不直接参与tau蛋白在Ser 262/356的磷酸化。这些结果表明，病理级联事件，包括升高的tau蛋白磷酸化水平在Ser 262/356和异常激活的CaMKII，协同工作，以促进tau蛋白介导的神经变性。
Abnormal deposition of the microtubule-associated protein tau is a common pathological feature of multiple neurodegenerative diseases, including Alzheimer's disease (AD), and plays critical roles in their pathogenesis. Disruption of calcium homeostasis and the downstream kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) coincides with pathological phosphorylation of tau in AD brains. However, it remains unclear whether and how dysregulation of CaMKII affects tau toxicity. Using a Drosophila model, we found that CaMKII promotes neurodegeneration caused by tau phosphorylated at the AD-associated sites Ser262/356. Overexpression of CaMKII promoted, while RNA-mediated knockdown of CaMKII and inhibition of CaMKII activity by expression of an inhibitory peptide suppressed, tau-mediated neurodegeneration. Blocking tau phosphorylation at Ser262/356 by alanine substitutions suppressed promotion of tau toxicity by CaMKII, suggesting that tau phosphorylation at these sites is required for this phenomenon. However, neither knockdown nor overexpression of CaMKII affected tau phosphorylation levels at Ser262/356, suggesting that CaMKII is not directly involved in tau phosphorylation at Ser262/356 in this model. These results suggest that a pathological cascade of events, including elevated levels of tau phosphorylated at Ser262/356 and aberrant activation of CaMKII, work in concert to promote tau-mediated neurodegeneration.