Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and.
Electron Microscopy Laboratory, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
J Neurosci. 2019 Sep 18;39(38):7628-7640. doi: 10.1523/JNEUROSCI.0313-19.2019. Epub 2019 Aug 12.
Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on α-synuclein (αS) homeostasis and related PD neuropathology remain unknown. Here, we used an αS tetramer-abrogating mouse model of PD (3K) that amplifies the familial E46K PD mutation to investigate the effects of female sex and brain-selective estrogen treatment on αS tetramerization and solubility, formation of vesicle-rich αS aggregates, dopaminergic and cortical fiber integrity, and associated motor deficits. In male 3K mice, the motor phenotype became apparent at ∼10 weeks and increased to age 6 months, paralleled by PD-like neuropathology, whereas 3K females showed a significant delay in onset. At 6 months, this beneficial phenotypic effect in 3K females was associated with a higher αS tetramer-to-monomer ratio and less decrease in dopaminergic and cortical fiber length and quantity. Brain-selective estrogen treatment in symptomatic 3K mice significantly increased the tetramer-to-monomer ratio, turnover by autophagy of aggregate-prone monomers, and neurite complexity of surviving DAergic and cortical neurons, in parallel with benefits in motor performance. Our findings support an upstream role for αS tetramer loss in PD phenotypes and a role for estrogen in mitigating PD-like neuropathology Brain-selective estrogen therapy may be useful in delaying or reducing PD symptoms in men and postmenopausal women. The mechanisms responsible for the male-to-female preponderance in Parkinson's disease (PD) are not well understood yet important for treatment efficacy. We previously showed that abrogating native α-synuclein (αS) tetramers produces a close PD model, including dopaminergic and cortical fiber loss and a progressive motor disorder responsive to l-DOPA. Here, we analyzed sex and use 10b-17β-dihydroxyestra-1,4-dien-3-one treatment of symptomatic 3K males, and demonstrate that the beneficial effects of female sex on PD-like neuropathology can be reinstated by elevating estrogen in the male brain. The study provides evidence that 17β-estradiol restores the tetramer-to-monomer ratio by autophagy turnover of excess αS monomers, vesicle and fiber integrity in brain regions critically involved in motor behavior. These data provide the basis for understanding sex differences in αS homeostasis and the development of therapeutic approaches to treating men and postmenopausal women with PD.
许多研究报告称，男性患帕金森病 (PD) 的风险更高，发病年龄更小。此外，帕金森病症状背后的神经病理过程可能在绝经前就已经开始，这表明基于雌激素的激素疗法可能会改变男性的这种高风险。然而，女性性激素或雌激素对α-突触核蛋白 (αS) 内稳态和相关 PD 神经病理学的影响尚不清楚。在这里，我们使用了一种 PD (3K) 的αS 四聚体破坏小鼠模型，该模型放大了家族性 E46K PD 突变，以研究雌性和脑选择性雌激素治疗对αS 四聚体化和可溶性、囊泡丰富的αS 聚集体形成、多巴胺能和皮质纤维完整性以及相关运动缺陷的影响。在雄性 3K 小鼠中，运动表型在大约 10 周时变得明显，并持续到 6 个月大，同时出现 PD 样神经病理学，而 3K 雌性小鼠的发病时间明显延迟。在 6 个月时，3K 雌性动物的这种有益表型效应与更高的αS 四聚体-单体比以及多巴胺能和皮质纤维长度和数量的减少有关。在有症状的 3K 小鼠中，脑选择性雌激素治疗显著增加了四聚体-单体比、通过自噬清除易聚集单体的周转率，以及存活的 DA 能和皮质神经元的神经突复杂性，与运动表现的改善平行。我们的研究结果支持αS 四聚体缺失在 PD 表型中的上游作用，以及雌激素在减轻 PD 样神经病理学中的作用。脑选择性雌激素治疗可能对延迟或减少男性和绝经后女性的 PD 症状有用。导致帕金森病 (PD) 男性优势的机制尚不清楚，但对治疗效果很重要。我们之前曾表明，破坏天然α-突触核蛋白 (αS) 四聚体可产生接近 PD 的模型，包括多巴胺能和皮质纤维丢失以及对 l-DOPA 敏感的进行性运动障碍。在这里，我们分析了 3K 雄性动物的性别和 10b-17β-二羟雌酮治疗，并证明了雌性对 PD 样神经病理学的有益影响可以通过提高雄性大脑中的雌激素来恢复。该研究为理解αS 内稳态中的性别差异以及为治疗男性和绝经后女性 PD 提供治疗方法提供了依据。
