Xia Danhao, Xiong Min, Yang Yingxu, Wang Xin, Chen Qiang, Li Sheng, Meng Lanxia, Zhang Zhentao
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
NPJ Parkinsons Dis. 2025 May 28;11(1):139. doi: 10.1038/s41531-025-00998-x.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) and the nigrostriatal dopaminergic neuronal degeneration. Depression is one of the most common non-motor symptoms of PD patients. However, the pathogenic connection between PD and depression is not well understood. Herein, we report that chronic stress upregulates the expression of α-syn in the mouse brain. Overexpression of α-syn in the hippocampus replicates depressive-like phenotypes, whereas the genetic deletion of α-syn enhances resistance to chronic stress. Furthermore, chronic stress in early life promoted the deposition of α-syn aggregates in a transgenic mouse model that overexpresses human A53T mutant α-syn (A53T mice). Chronic stress also exacerbated dopaminergic degeneration and motor impairments in A53T mice. Strikingly, α-syn inclusions were also observed in the brains of some aged non-transgenic mice subjected to chronic stress. Together, our findings suggest that chronic stress upregulates α-synuclein expression, resulting in depression-like behaviors and parkinsonism.
帕金森病（PD）是一种神经退行性疾病，其特征在于α-突触核蛋白（α-syn）的聚集以及黑质纹状体多巴胺能神经元变性。抑郁症是帕金森病患者最常见的非运动症状之一。然而，帕金森病与抑郁症之间的致病联系尚未完全明确。在此，我们报告慢性应激会上调小鼠大脑中α-syn的表达。海马体中α-syn的过表达会重现类似抑郁的表型，而α-syn的基因缺失则增强了对慢性应激的抵抗力。此外，早年的慢性应激促进了过表达人A53T突变型α-syn的转基因小鼠模型（A53T小鼠）中α-syn聚集体的沉积。慢性应激还加剧了A53T小鼠的多巴胺能变性和运动障碍。令人惊讶的是，在一些经受慢性应激的老年非转基因小鼠的大脑中也观察到了α-syn包涵体。总之，我们的研究结果表明，慢性应激会上调α-突触核蛋白的表达，导致类似抑郁的行为和帕金森综合征。
