title: Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo.
abstract: 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.
authors.affiliation: Department of Environmental Medicine, Center for Translational Neuromedicine, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Rappold
authors.affiliation: Department of Environmental Medicine, Center for Translational Neuromedicine, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Environmental Medicine, Center for Translational Neuromedicine, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.affiliation: Department of Clinical Neurobiology and Institute of Translational and Stratified Medicine, Plymouth University, John Bull Building, Plymouth PL6 8BU, UK.
authors.forename: Rebecca Z
authors.initials: RZ
authors.lastname: Fan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: de Mesy-Bentley
authors.affiliation: Department of Neurobiology, University of Chicago, 947 E. 58th Street, Chicago, Illinois 60637, USA.
authors.forename: Linan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, University of Chicago, 947 E. 58th Street, Chicago, Illinois 60637, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, New York 14642, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
authors.affiliation: 1] Department of Environmental Medicine, Center for Translational Neuromedicine, University of Rochester School of Medicine, 575 Elmwood Avenue, Rochester, New York 14642, USA [2] Department of Clinical Neurobiology and Institute of Translational and Stratified Medicine, Plymouth University, John Bull Building, Plymouth PL6 8BU, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D034281:Dynamins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000628:therapy*; D011494:Protein Kinases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine; D034281:Dynamins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C561064:FIS1 protein, mouse; C486391:Dnm1l protein, mouse