Interaction Between the Glymphatic System and α-Synuclein in Parkinson's Disease
Interaction Between the Glymphatic System and α-Synuclein in Parkinson's Disease
复制标题
帕金森病中类淋巴系统和 α-突触核蛋白之间的相互作用
DOI：
10.1007/s12035-023-03212-2
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发表时间：
2023-01-13
影响因子：
5.1
通讯作者：
Wang, Lin-Hui
中科院分区：
文献类型：
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作者：
Zhang, Yu;Zhang, Cui;Wang, Lin-Hui
类淋巴系统有助于清除大脑中的β - 淀粉样蛋白，在阿尔茨海默病中该系统受到破坏。然而，该系统是否参与α - 突触核蛋白（α - syn）的清除以及在帕金森病（PD）中是否受到抑制在很大程度上仍然未知。在黑质内注射重组人α - 突触核蛋白的小鼠中，我们发现通过水通道蛋白 - 4（AQP4）基因缺失或乙酰唑胺治疗抑制类淋巴系统会降低注射的α - 突触核蛋白从大脑中的清除率。在过表达人A53T - α - 突触核蛋白的小鼠中，我们发现AQP4缺乏加速了α - 突触核蛋白的积累，促进了多巴胺能神经元的丢失，并加速了类似帕金森病的症状。我们还发现A53T - α - 突触核蛋白的过表达降低了AQP4的表达/极化，并抑制了小鼠的类淋巴活动。该研究表明AQP4介导的类淋巴系统与脑实质α - 突触核蛋白之间存在密切相互作用，这意味着恢复类淋巴活动是延缓帕金森病进展的一个潜在治疗靶点。
The glymphatic system contributes to the clearance of amyloid-beta from the brain and is disrupted in Alzheimer's disease. However, whether the system is involved in the removal of alpha-synuclein (alpha-syn) and whether it is suppressed in Parkinson's disease (PD) remain largely unknown. In mice receiving the intranigral injection of recombinant human alpha-syn, we found that the glymphatic suppression via aquaporin-4 (AQP4) gene deletion or acetazolamide treatment reduced the clearance of injected alpha-syn from the brain. In mice overexpressing the human A53T-alpha-syn, we revealed that AQP4 deficiency accelerated the accumulation of alpha-syn, facilitated the loss of dopaminergic neurons, and accelerated PD-like symptoms. We also found that the overexpression of A53T-alpha-syn reduced the expression/polarization of AQP4 and suppressed the glymphatic activity of mice. The study demonstrates a close interaction between the AQP4-mediated glymphatic system and parenchymal alpha-syn, indicating that restoring the glymphatic activity is a potential therapeutic target to delay PD progression.