Neuroprotective Drug Discovery Center of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
Division of Clinical Pharmacy, Department of Pharmacy, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
Neuroscience. 2023 Jul 15;523:80-90. doi: 10.1016/j.neuroscience.2023.05.013. Epub 2023 May 29.
Epidemiological studies have demonstrated that women are less susceptible to Parkinson's disease (PD) than men. Estrogen exposure is hypothesized to confer protection against dopaminergic neuronal loss in patients with PD. Although the accumulation and propagation of α-synuclein (α-Syn) are closely linked to the clinical progression of PD, no relevant research has examined whether α-Syn proteostasis in the brain is altered in women after menopause. In this study, we established long-term ovariectomized (OVX) mice to simulate late post-menopause and investigated the expression and aggregation of α-Syn following the ovariectomy procedure. We observed that the OVX mice exhibited a significant increase in the expression and aggregation of α-Syn in the striatum and midbrain accompanied by impaired motor performance at 3 months after ovariectomy. The accumulation of α-Syn did not result in a significant loss of nigral dopaminergic neurons but did enhance autophagy and neuroglial activation. These findings imply that menopause may disrupt α-Syn proteostasis and exacerbate the accumulation of α-Syn in the basal ganglia circuit.
流行病学研究表明，女性患帕金森病 (PD) 的可能性低于男性。雌激素暴露被假设可以为 PD 患者的多巴胺能神经元损失提供保护。虽然α-突触核蛋白 (α-Syn) 的积累和传播与 PD 的临床进展密切相关，但尚无相关研究检查绝经后女性大脑中α-Syn 蛋白稳态是否发生改变。在这项研究中，我们建立了长期去卵巢 (OVX) 小鼠模型来模拟绝经后期，并在去卵巢手术后研究了α-Syn 的表达和聚集情况。我们观察到，去卵巢 3 个月后，OVX 小鼠纹状体和中脑中的α-Syn 表达和聚集显著增加，运动表现受损。α-Syn 的积累并没有导致黑质多巴胺能神经元的明显丧失，但增强了自噬和神经胶质激活。这些发现表明，绝经可能会破坏α-Syn 蛋白稳态，并加剧基底神经节回路中α-Syn 的积累。
