Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Mol Cell Neurosci. 2024 Jun;129:103934. doi: 10.1016/j.mcn.2024.103934. Epub 2024 May 1.
Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is sex-based and presence of sleeping disorders in PD also shows sex bias with a stronger phenotype in males. In addition to loss of dopamine-containing neurons in the striatum, arousal-related, orexin-containing neurons in the lateral hypothalamus (LH) are lost in PD, which could contribute to state-related disorders. As orexin has been shown to be involved in sleeping disorders and to have neuroprotective effects, we asked whether orexin could protect sleep-related LH neurons from damage putatively from the protein α-synuclein (α-syn), which is found at high levels in the PD brain and that we have shown is associated with putatively excitotoxic rises in intracellular calcium in brainstem sleep-controlling nuclei, especially in males. Accordingly, we monitored intracellular calcium transients induced by α-syn and whether concurrent exposure to orexin affected those transients in LH cells of the mouse brain slice using calcium imaging. Further, we used an assay of cell death to determine whether LH cell viability was influenced when α-syn and orexin were co-applied when compared to exposure to α-syn alone. We found that excitatory calcium events induced by α-syn were reduced in amplitude and frequency when orexin was co-applied, and when data were evaluated by sex, this effect was found to be greater in females. In addition, α-syn exposure was associated with cell death that was higher in males, and interestingly, reduced cell death was noted when orexin was present, which did not show a sex bias. We interpret our findings to indicate that orexin is protective to α-syn-mediated damage to hypothalamic neurons, and the actions of orexin on α-syn-induced cellular effects differ between sexes, which could underlie sex-based differences in sleeping disorders in PD.
帕金森病（PD）患者除了运动功能障碍的疾病定义症状外，还会经历睡眠障碍。PD 的患病率存在性别差异，并且 PD 中睡眠障碍的存在也表现出性别偏见，男性表现出更强的表型。除了纹状体中多巴胺能神经元的丧失外，外侧下丘脑（LH）中与觉醒相关的、含食欲素的神经元也在 PD 中丧失，这可能导致与状态相关的障碍。由于食欲素已被证明与睡眠障碍有关并有神经保护作用，我们想知道食欲素是否可以保护与睡眠相关的 LH 神经元免受潜在的蛋白质α-突触核蛋白（α-syn）的损伤，α-syn 在 PD 大脑中含量很高，我们已经表明它与脑干睡眠控制核内潜在的兴奋性细胞内钙升高有关，尤其是在男性中。因此，我们使用钙成像监测由α-syn 诱导的细胞内钙瞬变，以及食欲素是否会影响 LH 细胞中的这些瞬变。此外，我们使用细胞死亡测定法来确定当 α-syn 和食欲素同时应用时，与单独暴露于 α-syn 相比，LH 细胞活力是否受到影响。我们发现，当食欲素同时应用时，α-syn 诱导的兴奋性钙事件的幅度和频率降低，并且当按性别评估数据时，这种作用在女性中更大。此外，α-syn 暴露与细胞死亡有关，在男性中更高，有趣的是，当存在食欲素时，观察到细胞死亡减少，这没有表现出性别偏见。我们的研究结果表明，食欲素对下丘脑神经元的α-syn 介导的损伤具有保护作用，并且食欲素对 α-syn 诱导的细胞效应的作用在性别之间存在差异，这可能是 PD 中睡眠障碍的性别差异的基础。
