Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation
Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation
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DOI：
10.1111/j.1471-4159.2006.04059.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Ikezu, Tsuneya
中科院分区：
文献类型：
--
作者：
Sato, Shinji;Cerny, Ronald L.;Ikezu, Tsuneya
神经原纤维缠结是阿尔茨海默病（AD）的主要病理标志，由含有过度磷酸化tau蛋白的成对螺旋细丝（phf）组成。特异性激酶调节tau磷酸化，并与AD的发病机制密切相关。我们已经鉴定了位于染色体6p21.1上的人tau-tubulin kinase 1 （TTBK1）基因。TTBK1是一种丝氨酸/苏氨酸/酪氨酸激酶，在物种中保守，属于酪蛋白激酶1超家族。它在大脑中特异性表达，特别是在皮层和海马神经元的细胞质中。TTBK1以Mg2+和Mn2+依赖的方式磷酸化tau蛋白。磷酸化肽定位和免疫印迹分析证实TTBK1直接磷酸化tau蛋白的Ser198、Ser199、Ser202和Ser422位点，这些位点在phf中也被磷酸化。TTBK1也以剂量依赖的方式诱导人神经元细胞中的tau聚集。我们得出结论，TTBK1是一种神经元特异性双激酶，参与ad相关位点的tau磷酸化，也与tau聚集有关。
Neurofibrillary tangles, which are major pathological hallmarks of Alzheimer's disease (AD), are composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. Specific kinases regulate tau phosphorylation and are closely linked to the pathogenesis of AD. We have characterized a human tau-tubulin kinase 1 (TTBK1) gene located on chromosome 6p21.1. TTBK1 is a serine/threonine/tyrosine kinase that is conserved among species and belongs to the casein kinase 1 superfamily. It is specifically expressed in the brain, especially in the cytoplasm of cortical and hippocampal neurons. TTBK1 phosphorylates tau proteins in both a Mg2+- and a Mn2+-dependent manner. Phosphopeptide mapping and immunoblotting analysis confirmed a direct tau phosphorylation by TTBK1 at Ser198, Ser199, Ser202 and Ser422, which are also phosphorylated in PHFs. TTBK1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that TTBK1 is a neuron-specific dual kinase involved in tau phosphorylation at AD-related sites and is also associated with tau aggregation.