Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo

Dynamins Male Mice, Knockout Neuroscience and Neurobiology Dopamine Dopaminergic Neurons Parkinson Disease Mitochondrial Dynamics Article 3. Good health Mice, Inbred C57BL Mitochondrial Proteins Disease Models, Animal HEK293 Cells 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Animals Humans Protein Kinases
DOI: 10.1038/ncomms6244 Publication Date: 2014-11-05T13:13:03Z
ABSTRACT
AbstractMitochondrial 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.
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