α-synuclein致中脑黑质网状部PV阳性神经元退变引起行为改变的机制研究

中脑黑质网络部(SNr)是基底核信息的重要输出口，参与控制运动、认知和情感应激过程。SNr部位80%的GABA能神经元表达小清白蛋白(PV)。临床约有三分之一帕金森氏病(PD)患者SNr部位GABA神经元PV表达下降，提示PV减少很可能是PD病理发展的重要阶段。α-突触核蛋白(α-syn)诱导SNr部位PV+神经元退变的研究少见报道，我们前期的研究结果强烈提示α-syn诱导SNr部位PV+神经元退变，并引起行为改变。结合相关的文献报道和我们的研究积累，我们提出科学假说：α-syn导致钙离子内流超载，钙离子内环境稳态受到破坏，线粒体等亚细胞器受损，诱发ROS，激活NADPH氧化酶，产生过量的活性氧，抑制NMDAR，导致PV减少，PV+神经元退变。我们拟进一步验证我们的科学假设，阐明α-syn导致SNr部位PV+神经元退变的发生机制，为临床PD的早期诊断和干预治疗提供理论依据。

The pars reticulate of the substantia nigra (SNr) provides a main output nucleus of the basal ganglia where the final stage of information processing. Together with the internal segment of the globus pallidus, the SNr control motor, cognitive and emotional-motivational processes. The proportion of neurons in SNR is occupied by a majority of GABAergic neurons, and the majority of them (80%) express parvalbumin (PV). Degradation of PV occurred in in the midbrain is among 1/3 percent of Parkinson’s patients, which indicated that the PV degradation is a vital stage in the PD pathological process. Until now, there are very few reports about α-synuclein (α-syn) induces the PV+ neuron degeneration in the SNr. Our previous study strongly pointed out α-syn induced the PV+ neuron degeneration in the SNr accompany with behavioral change. Based on our previous studies, we speculate that α-syn could cause internal overload of calcium ions, calcium homeostasis is damaged and mitochondria destroyed, then induce the response of oxidative stress (ROS), activate NADPH oxidase with overproducing superoxide production, inhibit NMDA-R, reduce PV. All of these caused PV+ neuron degeneration. We design a new project to deeply validate our scientific assumptions in order to clarify the mechanism of the PV+ neuron degeneration.