铁死亡抑制剂 Fer-1 对帕金森病的影响研究

帕金森病(Parkinson's disease, PD)是全球第二大神经退行性疾病，近年来研究表明，帕金森病患者存在铁代谢异常。文章以果蝇为模式生物，利用Uas-Ga14系统靶向突变多巴胺能神经元(dopaminergic neuron, DA)中PINK1基因构建果蝇帕金森病模型。通过检测对照组( $ W^{1118} $)、模型组( $ PINK1^{B9} $)和铁死亡抑制剂(Ferrostatin-1, Fer-1)干预组( $ PINK1^{B9} $-Fer-1)3组果蝇的运动能力、脑中铁水平、活性氧(reactive oxygen species, ROS)、脂质过氧化水平和多巴胺能神经元数目以探究铁死亡在帕金森病中的作用。结果表明：模型组果蝇运动能力下降，脑内铁质量浓度增多，ROS及脂质过氧化水平上升，多巴胺能神经元数目下降；通过Fer-1干预可以有效改善运动表型，并降低ROS及脂质过氧化水平，提高多巴胺能神经元数目。综上所述，通过突变PINK1基因构建的帕金森病模型中存在细胞铁死亡，Fer-1治疗可以挽救相关症状。该文为后续研究帕金森病的病理机制提供新的方向。

Parkinson’s disease(PD) is the second most common neurodegenerative disease in the world. Recent studies have demonstrated the presence of dysfunctional iron metabolism in patients with PD. This study constructed a Drosophila PD model by targeting mutations in the PINK1 gene in dopaminergic neuron(DA) using the Uas-Ga14 system. To investigate the role of the inhibitor of ferroptosis in PD, the study examined the motor ability, iron level in the brain, reactive oxygen species(ROS) level, lipid peroxidation level and number of DA in three groups of Drosophila: control( $ W^{118} $), PD model( $ PINK1^{B9} $) and Ferrostatin-1(Fer1) treatment( $ PINK1^{B9} $-Fer-1) groups. The results showed that the model group of Drosophila had decreased motor ability, increased iron content in the brain, increased ROS and lipid peroxidation levels, and decreased number of DA compared with the control group. Meanwhile, adding the ferroptosis inhibitor Fer-1 could effectively improve the motor phenotype, reduce the levels of ROS and lipid peroxidation and increase the number of DA. In summary, ferroptosis was present in the PD model constructed by mutating the PINK1 gene, and the symptoms could be rescued by Fer-1 treatment. This finding provides a new direction for the subsequent study of the pathological mechanism of PD.