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<p>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.</p>

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Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月28日

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  • Danhao Xia,
  • Min Xiong,
  • Yingxu Yang,
  • Xin Wang,
  • Qiang Chen,
  • Sheng Li,
  • Lanxia Meng,
  • Zhentao Zhang

摘要

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.