解耦联蛋白2对胶质细胞功能和神经再生的调节与帕金森病的相关性研究

Mitochondrial uncoupling protein 2 (UCP2), which expressed in the inner membrane of mitochondria, is recognized to uncouple oxidative phosphorylation, inhibit reactive oxygen species (ROS) production and against oxidative damage. Our group had found UCP2 knockout exacerbated dopaminergic (DA) neuron degeneration in a MPTP/p mouse model, indicating that UCP2 may be involved in the pathogenesis of Parkinson's disease (PD). Currently, we found that UCP2 is also expressed in astrocytes and neural stem cells (NSCs). In the present study, we intend to investigate the regulatory effects of UCP2 on astrocyte-mediated oxidative stress, metabolic inflammation and gliotransmission with UCP2+/+ and UCP2-/- mice in vivo and in vitro. The modulation of UCP2 on NSC proliferation, survival, migration and differentiation will also be investigated in the project. We propose that UCP2 involves the pathogenesis of PD via regulating astrocytic function and neuroregeneration. These findings will give us an insight into the potential of UCP2 in the neuroprotection of PD.

线粒体解耦联蛋白2（Uncoupling protein 2, UCP2）是位于线粒体内膜上的质子转运蛋白，可使氧化磷酸化解耦联，减少ROS的产生并发挥抗氧化损伤作用。申请者在前期研究中发现UCP2缺失与帕金森病（Parkinson's disease, PD）的发生相关，新近又相继发现小鼠脑内星形胶质细胞和神经干细胞表达UCP2。本项目拟在前期研究基础上，应用已制备的UCP2敲除鼠建立MPTP/p PD模型，在整体、细胞和分子水平研究、阐明UCP2对中脑星形胶质细胞的能量代谢、氧化应激和胶质传递等功能的影响及对神经干细胞增殖、存活、迁移、分化的调节作用，揭示UCP2对胶质细胞功能和神经再生的调节与PD发生的相关性。研究成果不仅有助于深化对PD病理机制的认识，也为研发理想的多潜能神经保护剂提供新的靶标。

线粒体解耦联蛋白2（Uncoupling protein 2, UCP2）是位于线粒体内膜上的质子转运蛋白，与线粒体功能和全身能量代谢密切相关。本项目应用已制备的UCP2敲除鼠建立MPTP/p诱导的帕金森病（Parkinson’s disease, PD）模型，在整体、细胞和分子水平研究UCP2对中脑星形胶质细胞的能量代谢、氧化应激和胶质传递等功能的影响及对神经再生的调节作用。本项目研究发现除神经元外，星形胶质细胞和神经干细胞也表达UCP2。UCP2敲除取消其线粒体质子漏功能，增加ROS生成，一方面引起内质网应激（ER stress），导致caspase-12依赖的细胞凋亡；一方面激活NLRP3炎症小体，生成过量IL-1β，引起星形胶质细胞介导的神经炎症，最终导致多巴胺能神经元损伤。进一步研究发现全身代谢性炎症加重PD的神经损伤，且NLRP3炎症小体是调节PD小鼠成年神经再生的重要靶标。上述结果揭示了UCP2介导的胶质细胞功能和神经再生调节与PD发生、发展的相关性。研究成果不仅有助于深化对PD病理机制的认识，也为研发理想的多潜能神经保护剂提供新的靶标。