Abstract:
Parkinson\'s disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk, and venous thrombosis is a cause of sudden death in PD, suggesting targeting the Pink1/Parkin pathway in the periphery has therapeutic potential.
摘要:
帕金森病(PD)是最常见的进行性神经退行性运动障碍,是黑质致密质中多巴胺能神经元选择性丢失的结果。Pink1和Parkin是在线粒体质量控制中共同发挥作用的蛋白质,当它们携带功能丧失突变时,会导致家族性PD。虽然许多研究集中在PD的中枢神经系统改变上,外周对PD发病机制的贡献越来越受到重视.我们报道了Pink1/Parkin调节大鼠外周血单核细胞(PBMC)的糖酵解和线粒体氧化代谢。Pink1/Parkin缺乏症诱导循环淋巴细胞群的变化,即增加CD4+T细胞和减少CD8+T细胞和B细胞。Pink1/Parkin的缺失导致血液中血小板计数升高和血小板-T细胞聚集增加。血小板-淋巴细胞聚集体与血栓形成风险增加有关,静脉血栓形成是导致PD患者猝死的原因,提示靶向外周Pink1/Parkin通路具有治疗潜力。