情志应激诱导多巴胺能神经元ferroptosis增加帕金森病“易感性”研究

Parkinson's disease (PD) is a major neurodegenerative disease caused by the combination of genetic and environmental factors. Currently, there are no effective treatments or drugs to completely cure PD. Our previous studies found that individuals with the same PD genotypes possessed different susceptibility to PD under different emotional conditions. We hypothesize that emotional stress induced redox dysbalance sensitizes dopaminergic neurons to a novel type of programmed cell death – ferroptosis – and explore the mechanistic details involved. We will use respiratory metabolomics and oxidative lipidomics along with other advanced technologies to uncover the mechanisms through which emotional stress and activated HPA axis cause changes in the hormonal status, polyunsaturated lipid homeostasis, and intracellular redox balance, thereby inducing DJ-1 expression and ferroptosis in dopaminergic neurons. We will explore the signaling cascades in the ferroptotic program –TFR1/DMT1 or SLC7A11/GPX4. These mechanistic studies will be used to establish in vitro and in vivo model test-systems for screening of a variety of Chinese medicines or natural compounds as inhibitors of dopaminergic neuronal ferroptosis. The underlying molecular mechanisms will be explored for the most effective inhibitors. The results of this study will enrich the “emotional pathogenicity” theory and contribute to understanding of the specific pathological processes through which emotional stress promotes death of dopaminergic neurons and exacerbates PD. The results obtained will be used for the development of new prevention and treatment strategies against PD.

帕金森病（PD）是遗传内因和环境外因作用下引发的神经退行性疾病，目前无有效治疗方法，病理机制不明确。我们前期研究发现科学问题：具有相同PD基因型的个体在不同的情志状态对PD的‘易感性’不同，并提出科学假说：情志应激引起“肝风内动”增加PD“易感性”的机制可能与其增敏多巴胺能神经元发生一种新型程序性细胞死亡——铁凋亡（ferroptosis）有关。本项目拟采用氧化脂质组学等先进技术，深入研究情志应激兴奋HPA轴引起激素和细胞内氧化水平的变化，进而诱导DJ-1通过调节TFR1/DMT1或SLC7A11/GPX4信号通路引起多巴胺能神经元发生Ferroptosis的生物学机制，并在此基础上采用mechanism-based design策略筛选能抑制多巴胺能神经元ferroptosis的中药方剂及活性成分。研究结果将丰富“情志致病”理论的生物学基础研究，为PD的防治策略和药物开发提供科学依据。

《素问·举痛论》有云“百病生于气”。 本课题组长期从事情志致病生物医学基础研究，发现持续情志应激状态会导致机体多种生理机能的低下，包括导致神经退行性病变。帕金森病在中医学属于“颤证”范畴，《黄帝内经》中记载“诸风掉眩”，“掉”即震颤，认为情志应激可增加帕金森病（Parkinson’s disease，PD）症候的易感性。本课题从情志应激的角度，阐明导致帕金森病（Parkinson’s disease，PD）易感性增加的因素和机理这一科学问题。本课题利用多种转基因模型和基于LC-MS/MS的氧化磷脂组学技术，①以阐明情志应激增加PD“易感性”为研究主要研究目标，研究“肝郁气滞”生物效应与多巴胺能神经元铁死亡关联性，从整体、器官、细胞及分子生物学等层次，采用呼吸代谢组学、激素代谢组学和氧化脂质组学等先进关键技术，深入研究情志应激引起多巴胺能神经元发生铁死亡的生物学机制，提出应激激素是应激诱导PD易感的效应物质；②在揭示“肝郁气滞”导致PD“易感性”增加生物医学基础的同时，侧重研究情志应激增强多巴胺能神经元发生铁死亡的敏感性，进而增加PD“易感性”间的生物学机制，从分子水平揭示磷脂的过氧化是导致多巴胺能神经元发生铁死亡（ferroptosis）的直接原因，并在基因水平上发现脂氧合酶ALOX15是PD进程中磷脂过氧化增加导致铁死亡的关键靶标。本课题丰富了“情志致病”理论的生物学基础数据，有利于理解情志应激促进多巴胺能神经元的死亡或者PD的病理进程。本项目按照研究计划基本完成了项目设定的实验内容，在Signal Transduct Target Ther、Nat Commun、Nat Chem Biol、Cell Death Differ、Acta Pharmacol Sin等国际著名期刊发表影响因子大于10的高水平论文12篇，单篇最高影响因子38.104，培养博士后2名、博士研究生4名和硕士研究生8名，并且有望推动具有自主知识产权的PD辅助治疗中医药产品的开发和转化。