Hu Shanshan, Hu Meigui, Liu Jian, Zhang Bei, Zhang Zhen, Zhou Fiona H, Wang Liping, Dong Jianghui
Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou, People's Republic of China.
The Second School of Clinical Medicine, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong, People's Republic of China.
Neuropsychiatr Dis Treat. 2020 Mar 4;16:651-663. doi: 10.2147/NDT.S235562. eCollection 2020.
Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model.
Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed.
The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions.
These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.
帕金森病（PD）是第二常见的神经退行性疾病。α-突触核蛋白是路易小体和路易神经突的主要成分，是PD的病理标志。已知在PD中α-突触核蛋白会发生磷酸化（p-α-突触核蛋白），并且tau蛋白过度磷酸化（p-Tau）也是PD的一个病理特征。然而，PD中p-突触核蛋白与p-Tau之间的关系尚不清楚，尤其是在PD的MPTP模型中。本研究的目的是揭示它们在小鼠MPTP模型中的关系。
首先，分析p-α-突触核蛋白、α-突触核蛋白、p-Tau和Tau蛋白水平。然后，使用免疫印迹和免疫组织化学染色确定糖原合成酶激酶3β（GSK3β）的激活情况。最后，使用酪氨酸羟化酶（TH）染色和逆行标记评估多巴胺能神经变性，并标记小胶质细胞标志物。观察小胶质细胞激活和黑质纹状体通路变性。
结果显示，在PD小鼠模型的海马体和黑质中，p-α-突触核蛋白、α-突触核蛋白、p-Tau和Tau均上调。此外，p-α-突触核蛋白和p-Tau定位于海马体（Hippo）的黑质（SN）和齿状回（DG）的相同区域。GSK3β的激活形式（磷酸化GSK3β Y216）在多个脑区增加。向MPTP小鼠注射GSK3β抑制剂AZD1080可抑制p-Tau和p-GSK3β的表达并改善运动功能。
这些发现表明，在PD小鼠MPTP模型中，p-α-突触核蛋白和p-Tau蛋白是导致神经变性和运动功能障碍的关键病理事件。我们的数据表明，干扰GSK3β活性可能是治疗PD的有效方法。
