NMDA受体的激活在帕金森病黑质铁聚集中的作用机制研究

研究已证实黑质铁聚集是帕金森病（PD）多巴胺能神经元损伤的原因之一。我们发现PD黑质铁聚集与铁转入蛋白二价金属离子转运蛋白1（DMT1）及铁转出蛋白Ferroportin 1 (FPN1)的表达异常有关。文献报道NMDA受体的激活可以上调海马神经元的DMT1，但在PD的病理状态下，NMDA受体的激活与黑质铁聚集之间的关系如何尚不清楚。本项目应用多种技术方法，在MPTP制备的PD动物模型，NR1条件基因敲除小鼠及体外培养的多巴胺能神经元中，研究NMDA受体的激活对多巴胺能神经元DMT1，FPN1的表达及铁转运功能的影响，并深入探讨其机制，证实NMDA受体激活能够通过IRPs/IRE，NF-κB及Parkin等因素增加DMT1的表达，通过NO-Dexras1通路的激活增强DMT1的摄铁功能，还可以通过IRPs/IRE系统下调FPN1。本研究将为NMDA受体参与PD的发病机制提供全新的理论依据。

A growing body of evidence shows that the elevated iron levels in the substantia nigra pars compacta (SNpc) play a key role in the degeneration of dopamine neurons in Parkinson's disease (PD). The previous study in our laboratory showed that the misregulation of iron import protein divalent metal transporter 1 (DMT1) and iron export protein Ferroportin 1 (FPN1) were involved in this nigral iron accumulation in PD. Evidence also showed that the activation of NMDA recepter could up-regulate DMT1 in hippocampal neurons. However, the relationship between the activation of NMDA recepter and iron accumulation in the substantial nigra in PD was unknown. In this study, using MPTP-induced PD models, NR1 knockout mice and cultured dopamine neurons, we will explore the role of the activation of NMDA recepter in the expression of iron transporters DMT1, FPN1 and the function of iron transport in dopamine neurons, as well as the underlying mechanisms. We hypothesize that the stimulation of NMDA receptors could up-regulate DMT1 via NO-IRPs/IRE pathway or activating NF-κB or affecting the activity of parkin, enhance iron uptake via NO-Dexras1-DMT1 signaling cascade, and down regulate FPN1 via NO-IRPs/IRE pathway. This leads to the ultimate nigral iron accumulation in PD. This will provide new research results and strategies for the prevention and treatment of PD.