Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases.
Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases.
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DOI：
10.1371/journal.pone.0075025
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sidhu A
中科院分区：
文献类型：
--
作者：
Duka V;Lee JH;Credle J;Wills J;Oaks A;Smolinsky C;Shah K;Mash DC;Masliah E;Sidhu A
大多数神经退行性疾病含有过度磷酸化的Tau [p-Tau]。我们第一次检查了在帕金森病、路易体痴呆和阿尔茨海默病中Tau过度磷酸化的表位，并且还选择了Tau激酶。使用市售的抗Tau的20种不同磷酸化表位的抗体，通过免疫印迹分析帕金森病、路易体痴呆、阿尔茨海默病和帕金森病的纹状体的死后额叶皮质。还筛选了主要的Tau激酶。将患病组织中的结果与未患病对照进行比较。在阿尔茨海默病中，Tau在p-Tau的所有20个表位处被过度磷酸化。在路易体痴呆症中，p-Tau形成发生在6个位点，与阿尔茨海默病重叠30%，而在帕金森额叶皮质（一个不退化的区域）中，仅在3个表位处观察到Tau过度磷酸化，表明与阿尔茨海默病重叠15%。在帕金森病纹状体中，一个经历相当大的神经变性的区域，Tau在10个表位处过度磷酸化，与阿尔茨海默病共享50%的重叠。在帕金森病和路易体痴呆的额叶皮质之间，只有两个共同的p-Tau表位。在帕金森病的纹状体中，在3个连续位点处存在3个Tau过度磷酸化的簇，而在路易体痴呆中检测到两个这样的簇;这样的簇破坏线粒体的轴突运输，引起微管重塑并导致细胞死亡。p-GSK-3β是一种主要的Tau激酶，在所有检查的脑区都被激活，但路易体痴呆除外。其他Tau激酶的激活在所有脑区都有发现，但没有明确的激活模式。我们的研究表明，这三种神经退行性疾病各自具有p-Tau形成的特征特异性特征，这可能有助于理解疾病的起源和开发一组特异性生物标志物。
Most neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson’s disease, dementia with Lewy bodies and Alzheimer’s disease, and also select Tau kinases. Postmortem frontal cortex from Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease and striata from Parkinson’s disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls. In Alzheimer’s disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer’s disease, while in Parkinson’s frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer’s disease. In Parkinson’s disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer’s disease. Between frontal cortex of Parkinson’s disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson’s disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation. Our studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.
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影响因子：
4.8
作者：
Hashimoto, M;Bar-on, P;Masliah, E
通讯作者：
Masliah, E
影响因子：
4.8
作者：
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影响因子：
3.7
作者：
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3.3
作者：
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3.3
作者：
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