Drp1的调控对PINK1突变转基因果蝇的保护作用

Drp1 Protects PINK1 Mutant Drosophila

帕金森病(PD)是以黑质致密部多巴胺神经元选择性减少和胞浆内路易小体的形成为特征的神经退行性疾病。研究发现,PTEN诱导激酶1(PINK1)基因突变导致家族性早发型帕金森病的发生。在转基因果蝇中,PINK1功能丢失导致间接飞行肌缺陷,线粒体结构、功能障碍,多巴胺神经元丢失。本研究在PINK1突变PD转基因果蝇中,进行发动蛋白相关蛋白1(Drp1)过表达和敲低,探索Drp1对PD转基因果蝇的保护作用及其可能机制。本研究选用MHC-Gal4/UAS系统的PD转基因果蝇模型,特异性启动PINK1B9基因于果蝇肌肉组织中表达;运用Drp1基因过表达和RNA干扰干预PINK1B9转基因果蝇,研究其对PD转基因果蝇的作用。结果显示,不论过表达Drp1还是Drp1敲低均可挽救PINK1突变转基因果蝇,降低翅膀异常率,改善飞行能力,恢复间接飞行肌排列,调节线粒体形态,提高ATP生成量,上调NDUFS3蛋白表达水平。本文结果提示,Drp1的调控挽救PINK1突变转基因果蝇与线粒体呼吸链有关。

Parkinson＇s disease（ PD） is a neurodegenerative disease characterized by selective reduction of dopamine neurons in substantia nigra,where Lewy bodies are formed in the cytoplasm. Evidence indicated that mutations in PTEN-induced kinase 1（ PINK1） caused familial,early onset Parkinson＇s disease. In Drosophila melanogaster,loss of PINK1 leads to indirect flight muscle defects,swollen and dysfunctional mitochondria,energy depletion,and dopaminergic neuron loss. In this study,a MHCGAL4 promoter was used to make muscle-specific expression in PINK1B9 drosophila,and then Drp1 overexpression and RNA interference were performed. The results showed that either overexpression or knockdown of Drp1 protected the PINK1 mutant flies. Abnormal wing posture was reduced,flight ability and disordered muscle fibers were restored. NDUFS3 protein and ATP levels were increased. These results indicated that Drp1 protected PINK1 mutant Drosophila against mitochondrial dysfunction.