Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's disease.
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DOI：
10.1371/journal.pone.0017953
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发表时间：
2011-03-21
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：
Wills J;Credle J;Haggerty T;Lee JH;Oaks AW;Sidhu A
Tau蛋白通路导致阿尔茨海默病的退行性变化，并且有证据表明它们也参与帕金森病 [PD] 的神经退行性病理学。我们检查了 α-突触核蛋白 (α-Syn) A53T 突变小鼠纹状体的 tau蛋白病变化。在成年 A53T α-Syn 小鼠的纹状体中观察到 α-Syn 水平升高。伴随着过度磷酸化 Tau [p-Tau] 的增加，其磷酸化位点为 Ser202、Ser262 和 Ser396/404，这些毒性位点也出现在阿尔茨海默病中。活性 p-GSK-3β 增加，Tyr216 过度磷酸化，Tyr216 是一种已知在多个位点磷酸化 Tau 的主要激酶。 A53T 突变小鼠中 Tau 过度磷酸化的位点与 PD 患者死后纹状体中观察到的位点相似，证明了它们的病理生理学相关性。无论是 A53T 小鼠还是人类 PD，p-Tau 的增加都不是由于蛋白磷酸酶的改变所致，这表明这些蛋白与 tau 蛋白病无关。用 Triton X-100 提取纹状体显示 α-Syn 寡聚形式大幅增加，表明 α-Syn 已在突变小鼠中形成聚集体。此外，还发现 p-GSK-3β 和 pSer396/404 水平的增加与聚集的 α-Syn 相关。测量蛋白质与细胞骨架蛋白结合的差异溶解表明，A53T 突变小鼠中的 p-Tau 未与细胞骨架蛋白结合，这与过度磷酸化后 p-Tau 从微管解离一致。有趣的是，α-Syn 仍然与细胞骨架紧密结合，而 p-GSK-3β 则出现在无细胞骨架的部分中。免疫组织化学研究表明，α-Syn、pSer396/404 Tau 和 p-GSK-3β 彼此共定位并聚集并积累成大的包涵体，导致黑质神经元细胞死亡。总之，这些数据表明 A53T α-Syn 突变小鼠纹状体内的 tau 蛋白病状态升高，表明 tau 蛋白病是突触核蛋白病的常见特征。
Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.
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影响因子：
16.2
作者：
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通讯作者：
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