Rappold Phillip M, Cui Mei, Grima Jonathan C, Fan Rebecca Z, de Mesy-Bentley Karen L, Chen Linan, Zhuang Xiaoxi, Bowers William J, Tieu Kim
Department of Environmental Medicine, Center for Translational Neuromedicine, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, New York 14642, USA.
Department of Clinical Neurobiology and Institute of Translational and Stratified Medicine, Plymouth University, John Bull Building, Plymouth PL6 8BU, UK.
Nat Commun. 2014 Nov 5;5:5244. doi: 10.1038/ncomms6244.
Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson's disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission and fusion has considerable potential for treating human diseases. To determine the therapeutic impact of targeting these pathways on PD, we used two complementary mouse models of mitochondrial impairments as seen in PD. We show here that blocking mitochondrial fission is neuroprotective in the PTEN-induced putative kinase-1 deletion (PINK1(-/-)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. Specifically, we show that inhibition of the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) using gene-based and small-molecule approaches attenuates neurotoxicity and restores pre-existing striatal dopamine release deficits in these animal models. These results suggest Drp1 inhibition as a potential treatment for PD.
线粒体功能障碍在家族性和散发性帕金森病（PD）中均有报道。然而，目前针对该途径的有效治疗方法并不充分。最近的研究表明，调控线粒体分裂和融合过程在治疗人类疾病方面具有巨大潜力。为了确定靶向这些途径对帕金森病的治疗效果，我们使用了两种与帕金森病中所见线粒体损伤互补的小鼠模型。我们在此表明，在PTEN诱导的假定激酶-1缺失（PINK1(-/-)）和1-甲基-4-苯基-1,2,3,6-四氢吡啶小鼠模型中，阻断线粒体分裂具有神经保护作用。具体而言，我们表明，使用基于基因和小分子的方法抑制线粒体分裂GTP酶动力相关蛋白-1（Drp1）可减轻神经毒性，并恢复这些动物模型中先前存在的纹状体多巴胺释放缺陷。这些结果表明抑制Drp1可能是治疗帕金森病的一种方法。
