铁与Alpha-突触核蛋白相互作用共同参与帕金森病的细胞分子机制

Both iron and alpha-synuclein accumulation are one of hallmarks of Parkinson's disease (PD). Alpha-synuclein aggregation is often accompanied by abnormal accumulation of iron, indicating that there is a certain link between iron and alpha-synuclein aggregation. The present study, from a quite novel perspective, aims to explore the cellular and molecular mechanisms of the iron and alpha-synuclein interaction. Using different PD animal models and alpha-synuclein transgenic animals, we examine whether iron accumulation starts in the lower brainstem progressing into the central nervous system through anatomically connected structures, just as the regional distribution of alpha-synuclein described in Braak stage. The correlation among the motor and non-motor symptoms, neurotransmitter systems associated with PD and the distribution patterns of iron and alpha-synuclein during PD progress are all studied. The mechanisms underlying how iron promotes alpha-synuclein aggregation and how alpha-synuclein regulates iron metabolism are also investigate. The neuroprotective effects of some anti-PD drugs which have the properties of both iron chelation and reducing alpha-synuclein aggregation are also studied. This project aims to clarify the interaction between iron and alpha-synuclein, which are two specific factors in PD pathogenesis, thus providing powerful evidence on etiology and promising strategies on prevention and therapy of PD.

帕金森病（PD）的特异标志物alpha-突触核蛋白的异常聚集往往伴有铁的沉积，说明铁与Alpha-突触核蛋白聚集之间存在一定联系。为了阐明两者相互作用共同参与PD的细胞分子机制，本项目拟在不同的PD动物模型和alpha-突触核蛋白转基因动物上，研究铁的沉积是否与Braak 分级描述的alpha-突触核蛋白一样，存在从低位脑到高位脑的渐变过程，揭示PD非运动症状与运动症状，递质系统的变化与铁和alpha-突触核蛋白进展的相关性。进一步阐明铁促进alpha-突触核蛋白的聚集机制以及alpha-突触核蛋白如何参与调节铁代谢。同时，本研究从既能螯合铁，又能降低alpha-突触核蛋白聚集的角度出发，阐明抗PD复合制剂的神经保护作用。本研究以突破常规的思路，阐明铁的沉积与alpha-突触核蛋白的聚集之间的相互作用及其机制，为阐明PD的病因并为PD的防治提供全新的研究结果和防治新策略。

帕金森病（PD）的特异标志物alpha-突触核蛋白（α-syn）的异常聚集往往伴有铁的沉积，说明铁与α-syn聚集之间存在一定联系。为了阐明两者相互作用共同参与PD的细胞分子机制，本项目在不同的PD动物模型和α-syn转基因动物上，研究了铁的沉积与α-syn从低位脑到高位脑的渐变过程，揭示了PD非运动症状与运动症状，递质系统的变化与铁和α-syn进展的相关性。阐明了铁促进α-syn的聚集机制以及α-syn如何参与调节铁代谢，同时，本研究从既能螯合铁，又能降低α-syn聚集的角度出发，阐明抗PD复合制剂的神经保护作用。该研究揭示：与α-syn从低位脑到高位脑的渐变过程不同，铁选择性的在黑质（SN）沉积且出现的时间较早，因此开发早期检测脑铁沉积的方法，将有助于将诊断的时间提前，有利于早期干预PD。PD非运动症状出现可能与迷走神经背核等脑区神经元内α-syn聚集有关，迷走神经背核神经元损伤可能造成PD病人血浆ghrelin下降，因此ghrelin可能成为PD早期诊断的靶点。铁沉积通过多种机制促进α-syn表达和聚集，而α-syn作为铁还原酶调节SN的铁代谢，α-syn表达上调和聚集可进一步加重神经元内的铁沉积，引起细胞氧化应激和铁死亡，由此导致恶性循环。迷迭香酸等制剂既能螯合铁又能降低α-syn聚集发挥神经保护作用。除此以外，本项目创新性地提出缺氧诱导因子2α的激活导致的星形胶质细胞铁转运加快可能是黑质铁沉积的来源。本项目利用多组学（磷酸化蛋白组学、蛋白组学和转录组学）与生物信息学相结合的方法，已经筛选得到了新的、重要的铁死亡调节因子，以期为PD的防治提供靶点。本研究以突破常规的思路，阐明铁的沉积与α-syn的聚集之间的相互作用及其机制，为阐明PD的病因并为PD的防治提供全新的研究结果和防治新策略。