Wu Qimei, Yang Xiaoyu, Zhang Yu, Zhang Lei, Feng Linyin
CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
Exp Neurol. 2016 Nov;285(Pt A):61-71. doi: 10.1016/j.expneurol.2016.09.004. Epub 2016 Sep 13.
Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice). We show that when exposed to CMS, male, but not female, A53T Tg mice developed profound motor disabilities and exhibited olfactory sensitivity deficits. Pathological analysis also identified robust dopaminergic neuron degeneration and strong reduction of dopamine levels in A53T Tg male mice who underwent CMS treatment. Systematic examination of the abnormal aggregation of α-synuclein revealed a profound increase of inclusion in A53T Tg male mice subject to CMS resembling key pathological changes of PD. An insight into the mechanism underlying stress leading to the acceleration of neurodegeneration in those with genetic susceptibility, was revealed by evidence of microglia activation and elevated pro-inflammatory factor levels in A53T Tg male mice following CMS. Notably, these effects of CMS on the pathogenesis of PD showed a remarkable sexual dimorphism: only male A53T Tg mice exhibited exacerbation of the progression of PD. However, the molecular and cellular bases for this difference remains to be elucidated. Our results indicate a causative role for chronic mild stress using a PD animal model. Based on these findings, we propose that CMS acts as an environmental risk factor that leads to neuroinflammation and progressive neurodegeneration on a background of PD susceptibility.
日常压力与多种疾病风险增加相关，众多研究已提供证据表明环境压力会对中枢神经系统产生有害影响。然而，慢性压力是否会加剧帕金森病（PD）的进展仍不清楚。为了探究这一假设，我们在过表达人类A53T突变α-突触核蛋白的转基因小鼠品系（A53T转基因小鼠）中，确定了慢性轻度应激（CMS）对PD发病机制的影响。我们发现，暴露于CMS时，雄性而非雌性A53T转基因小鼠出现了严重的运动障碍并表现出嗅觉敏感性缺陷。病理分析还发现，接受CMS治疗的A53T转基因雄性小鼠存在明显的多巴胺能神经元变性以及多巴胺水平大幅降低。对α-突触核蛋白异常聚集的系统检查显示，遭受CMS的A53T转基因雄性小鼠中的包涵体显著增加，类似于PD的关键病理变化。对导致具有遗传易感性者神经退行性变加速的应激潜在机制的深入研究发现，CMS后A53T转基因雄性小鼠存在小胶质细胞活化和促炎因子水平升高的证据。值得注意的是，CMS对PD发病机制的这些影响表现出显著的性别差异：只有雄性A53T转基因小鼠的PD进展加剧。然而，这种差异的分子和细胞基础仍有待阐明。我们的结果表明，在PD动物模型中慢性轻度应激具有致病作用。基于这些发现，我们提出CMS作为一种环境风险因素，在PD易感性背景下导致神经炎症和进行性神经退行性变。
