Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease.
Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease.
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DOI：
10.1111/j.1460-9568.2011.07660.x
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Sidhu A
中科院分区：
文献类型：
--
作者：
Haggerty T;Credle J;Rodriguez O;Wills J;Oaks AW;Masliah E;Sidhu A
尽管临床上不同的疾病，但tau蛋白病和突触核蛋白病具有共同的起源和机制，导致神经元内重叠的退行性变化。在帕金森病[PD]和痴呆PD的人死后纹状体中，我们最近描述了tau蛋白病水平升高，其指数为过度磷酸化Tau [p-Tau]增加。在此，我们评估了在PDGF启动子下过表达人α-突触核蛋白的PD转基因动物模型的纹状体中的tau蛋白病。在11个月大时，注意到转基因小鼠中p-Tau的大幅度和进行性增加，在使人联想到阿尔茨海默病的位点处过度磷酸化，沿着α-突触核蛋白和p-GSK-3β水平升高，p-GSK-3β是参与Tau过度磷酸化的主要激酶。对纹状体的Triton X-100差异提取显示，Tg小鼠中存在聚集的α-Syn，沿着p-Tau和p-GSK-3β，这也通过免疫组织化学证实。在p-Tau形成后，Tau和MAP 1都从细胞骨架上解离，这与这些细胞因子结合蛋白结合微管的能力减弱一致。还观察到游离微管蛋白和肌动蛋白的增加，表明细胞骨架重塑和不稳定。转基因动物的体内磁共振成像显示转基因小鼠的脑体积减少，表明实质性萎缩。从免疫组织化学研究中，发现α-突触核蛋白、p-Tau和p-GSK-3β过表达并共定位于大包涵体中，使人联想到Lewy小体。在这些PDGF-α-突触核蛋白小鼠中观察到的tau蛋白病的升高状态进一步证实了帕金森病可能是一种tau蛋白病。
Although clinically distinct diseases, tauopathies and synucleinopathies share common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson’s disease [PD] and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau [p-Tau]. Here we assessed tauopathy in striatum of a transgenic animal model of PD, overexpressing human α-synuclein under the PDGF promoter. At 11 months of age, large and progressive increases in p-Tau in transgenic mice, hyperphosphorylated at sites reminiscent of Alzheimer’s disease, were noted, along with elevated levels of α-synuclein and p-GSK-3β, a major kinase involved in hyperphosphorylation of Tau. Differential Triton X-100 extraction of striata showed the presence of aggregated α-Syn in the Tg mice, along with p-Tau and p-GSK-3β, which was also confirmed through immunohistochemistry. After p-Tau formation, both Tau and MAP1 dissociated from the cytoskeleton, consistent with diminished ability of these cytoskeleton-binding proteins to bind microtubules. Increases in free tubulin and actin were also noted, indicative of cytoskeleton remodeling and destabilization. In vivo magnetic resonance imaging of the transgenic animals showed a reduction in brain volume of transgenic mice indicating substantial atrophy. From immunohistochemical studies, α-synuclein, p-Tau and p-GSK-3β were found to be overexpressed and co-localized in large inclusion bodies, reminiscent of Lewy bodies. The elevated state of tauopathy seen in these PDGF-α-synuclein mice provides further confirmation that Parkinson’s may be a tauopathic disease.
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