Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo

Phillip M. Rappold, Mei Cui, Jonathan C. Grima, Rebecca Z. Fan, Karen L. de Mesy-Bentley, Linan Chen, Xiaoxi Zhuang, William J. Bowers and Kim Tieu ()
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Phillip M. Rappold: Center for Translational Neuromedicine, University of Rochester School of Medicine
Mei Cui: Center for Translational Neuromedicine, University of Rochester School of Medicine
Jonathan C. Grima: Center for Translational Neuromedicine, University of Rochester School of Medicine
Rebecca Z. Fan: Plymouth University
Karen L. de Mesy-Bentley: University of Rochester Medical Center
Linan Chen: University of Chicago
Xiaoxi Zhuang: University of Chicago
William J. Bowers: Center for Neural Development and Disease, University of Rochester Medical Center
Kim Tieu: Center for Translational Neuromedicine, University of Rochester School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6244

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