Phosphorylation of tau by fyn: Implications for Alzheimer's disease
Phosphorylation of tau by fyn: Implications for Alzheimer's disease
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DOI：
10.1523/jneurosci.4162-03.2004
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发表时间：
2004-03-03
影响因子：
5.3
通讯作者：
Ksiezak-Reding, H
中科院分区：
文献类型：
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作者：
Lee, G;Thangavel, R;Ksiezak-Reding, H
丝氨酸和苏氨酸上tau蛋白的异常磷酸化是阿尔茨海默病（AD）神经原纤维缠结的一个标志性特征。tau蛋白可以在酪氨酸上磷酸化的发现以及β信号转导涉及酪氨酸磷酸化的证据使我们质疑tau蛋白的酪氨酸磷酸化是否发生在神经退行性过程中。在这项研究中，我们确定了人tau tyr18被src家族酪氨酸激酶fyn磷酸化。通过开发特异性phospho-tyr18的多克隆和单克隆探针，我们发现tyr18位点的tau磷酸化发生在小鼠的早期发育阶段，但在成年小鼠中不存在。我们的磷酸特异性探针还显示，配对的螺旋丝制剂表现出对磷酸酪氨酸特异性蛋白磷酸酶处理敏感的磷酸酪氨酸18反应性。此外，免疫细胞化学研究表明，酪氨酸磷酸化的tau蛋白存在于阿尔茨海默病大脑的神经原纤维缠结中。然而，染色模式排除了神经丝和营养不良的神经突，这表明酪氨酸磷酸化的tau在AD大脑中的分布方式与其他异常磷酸化的tau不同。我们还发现证据表明，在退化的神经元中存在差异磷酸化的tau蛋白。我们的数据为fyn在神经退行性过程中的作用提供了新的支持。
The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that Abeta signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.