PLA2G6基因突变所致疾病亚型的临床表现虽然差异大，但影像学上脑内均可有铁沉积的现象，其具体机制仍不明确。研究表明铁死亡在帕金森病多巴胺能神经元丢失中发挥作用，本团队前期亦发现抑制iPLA2β磷脂酶活性可导致细胞内铁转运异常，提示iPLA2β磷脂酶活性下降可导致铁代谢的紊乱，最终导致神经变性。本项目拟在前期研究基础上，利用构建成功的PLA2G6基因操作小鼠模型及相关细胞系，通过干预iPLA2β酶活性、转染携带PLA2G6基因不同突变的病毒等方式，应用RT-PCR、Western blot、免疫组化等分子生物学方法，明确PLA2G6基因变异是否通过铁代谢异常导致铁沉积，是否通过诱导促铁死亡通路或减弱抑制铁死亡通路导致铁死亡，进一步探讨铁螯合剂或铁死亡抑制剂是否对PLA2G6基因变异导致的神经变性具有治疗作用，深入、系统地探讨PLA2G6基因变异导致铁沉积和铁死亡的作用机制。

The mutation of PLA2G6 gene can lead to a class of clinical heterogeneity of the disease which can appear in the imaging of iron deposit among brain and underlying mechanism remains unclear. Studies have shown that iron death plays a role in the loss of dopaminergic neurons in Parkinson's disease. Our team also found that inhibition the phospholipase activity of iPLA2β can lead to abnormal intracellular iron transport, suggesting that a decrease in iPLA2β phospholipase activity may lead to disruption of iron metabolism, eventually leading to nerve transsexual. On the basis of the previous studies, this project intends to use the constructed PLA2G6 gene manipulated mouse model and related cell lines, through the intervention of iPLA2β enzyme activity, transfection of viruses with different PLA2G6 mutations and other means, using RT-PCR, Western blot, Immunohistochemistry and other molecular biology methods to determine whether mutation of PLA2G6 lead to iron deposition by abnormal iron metabolism, whether the mutation of PLA2G6 induce iron death pathway or decrease the iron death pathway to lead to ferroptosis. To further explore whether the iron chelator or iron death inhibitor has a therapeutic effect on the neurodegeneration induced by PLA2G6 gene mutation, and to explore in depth the mechanism of the PLA2G6 gene mutation leading to iron deposition and iron ferroptosis.