星形胶质细胞铁代谢参与帕金森病黑质铁聚集的机制研究

Nigral iron accumulation plays a key role in Parkinson’s disease (PD). Astroctytes are responsible for iron transport across the blood-brain barrier and maintain the iron homeostasis in different brain regions. Howerver, the mechanisms of iron metabolism in neurons have received considerable attention, but little is known about iron metabolism in astroctyes. Our previous results show that the regulation of iron metabolism in neurons and astrocytes are different. 6-hydroxydopamine (6-OHDA) up-regulates iron import and down-regulates iron export in nigral domaminergic neurons, thus leading to cellular iron accumulation. While 6-OHDA promotes iron traffic in astrocytes by up-regulating both iron import and export. Therefore, astrocytes may be “iron pump”, and the enhanced iron traffic in astrocytes may be the source of iron accumulated in dopaminergic neurons. In this study, using in vitro blood brain barrier model, astrocytes-neurons co-culture system, gene knock-out mice and PD animal model induced by 6-OHDA, we aim to examine the hypothesis that astroctyes are a kind of iron supply cells, which provide excess iron for dopaminergic neurons to accumulate in the substantia nigra. 6-OHDA that may be produced by auto-oxidation in dopaminergic neurons, promotes iron traffic in astrocytes, the mechanism of which is through protein kinase C mediated activation of hypoxia-inducible factors in astroctyes. The study is to explore the mechanisms of iron metabolism in astrocytes and its role in the nigral iron accumulation in PD, thus providing insight into the control of astrocytes function to protect neurons as therapeutic strategies of PD.

黑质铁聚集是帕金森病（PD）发病的关键因素。星形胶质细胞（AS）在铁跨血脑屏障的转运及脑铁稳态的维持中发挥重要作用。然而铁代谢的研究多集中在神经元，AS铁代谢的调控尚不明确。我们前期研究发现AS与多巴胺（DA）能神经元铁代谢的调节并不相同，神经毒素6-OHDA增强DA能神经元铁转入，降低铁转出造成铁聚集；但6-OHDA却能同时增强AS铁转入与转出过程，增强其铁转运能力。AS可能是“铁泵”，其泵铁的增加可能是黑质DA能神经元聚集铁的来源。本研究拟在血脑屏障模型以及AS与神经元共培养体系，铁基因敲除小鼠和PD小鼠模型上证实“AS可能是铁泵”这一推断，其铁转运的加快是神经元聚集铁的来源；DA自身氧化产生的6-OHDA加快了AS铁的转运，该过程与蛋白激酶C介导的缺氧诱导因子异常激活有关。本研究不仅使我们对PD黑质铁聚集机制了解日臻完善，而且对调控AS的功能使其向保护神经元方向发展有重要的推动作用。

黑质铁聚集是帕金森病（PD）发病的关键因素。星形胶质细胞（AS）在铁跨血脑屏障的转运及脑铁稳态的维持中发挥重要作用。然而铁代谢的研究多集中在神经元，AS铁代谢的调控尚不明确。我们前期研究发现AS与多巴胺（DA）能神经元铁代谢的调节并不相同，神经毒素6-OHDA增强DA能神经元铁转入，降低铁转出造成铁聚集；但6-OHDA却能同时增强AS铁转入与转出过程，增强其铁转运能力。AS可能是“铁泵”，其泵铁的增加可能是黑质DA能神经元聚集铁的来源。为证实该假说，本研究在血脑屏障模型以及AS与神经元共培养体系，铁基因敲除小鼠和PD小鼠模型上揭示了6-OHDA加快AS铁转运功能的机制，证实了“AS可能是铁泵”这一推断。该研究揭示：6-OHDA引起星形胶质细胞铁转运能力增强是由缺氧诱导因子2α（HIF-2α）激活引起的而非缺氧诱导因子1α（HIF-1α）的激活引起。在星形胶质细胞中，PKC途径参与 6-OHDA 对星形胶质细胞 HIF-2α的激活，可能与ROS和NO激活PKCδ有关，从而上调铁转入蛋白二价金属离子转运蛋白1（DMT1）和铁转出蛋白ferroportin1（FPN1）表达，使铁转运能力增强。星形胶质细胞铁转运能力的增强起到“铁泵”的作用，6-OHDA加快星形胶质细胞铁转运是神经元铁沉积铁的来源。黑质DA自身氧化应激可能加快了星形胶质细胞铁转运过程，导致黑质DA神经元铁沉积，进而造成神经元变性死亡，引起PD。除此以外，本项目还对胶质细胞在脑铁代谢中的作用进行了致炎/抗炎和保护DA能神经元的全新诠释，提出乳铁蛋白，脑肠肽和白藜芦醇等生物活性物质能通过降低脑铁水平发挥神经保护作用。α-突触核蛋白与前炎性因子能激活小胶质细胞并影响小胶质细胞铁代谢造成小胶质细胞铁聚集。本研究不仅使我们对PD黑质铁聚集机制了解日臻完善，而且对调控AS的功能使其向保护神经元方向发展有重要的推动作用。