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Title: Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Authors: Richardson, Jason R; Caudle, W Michael; Guillot, Thomas S; Watson, Jodi L; Nakamaru-Ogiso, Eiko; Seo, Byoung Boo; Sherer, Todd B; Greenamyre, J Timothy; Yagi, Takao; Matsuno-Yagi, Akemi; Miller, Gary W

Published In Toxicol Sci, (2007 Jan)

Abstract: Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice and nonhuman primates causes a parkinsonian disorder characterized by a loss of dopamine-producing neurons in the substantia nigra and corresponding motor deficits. MPTP has been proposed to exert its neurotoxic effects through a variety of mechanisms, including inhibition of complex I of the mitochondrial respiratory chain, displacement of dopamine from vesicular stores, and formation of reactive oxygen species from mitochondrial or cytosolic sources. However, the mechanism of MPTP-induced neurotoxicity is still a matter of debate. Recently, we reported that the yeast single-subunit nicotinamide adenine dinucleotide (reduced) dehydrogenase (NDI1) is resistant to rotenone, a complex I inhibitor that produces a parkinsonian syndrome in rats, and that overexpression of NDI1 in SK-N-MC cells prevents the toxicity of rotenone. In this study, we used viral-mediated overexpression of NDI1 in SK-N-MC cells and animals to determine the relative contribution of complex I inhibition in the toxicity of MPTP. In cell culture, NDI1 overexpression abolished the toxicity of 1-methyl-4-phenylpyridinium, the active metabolite of MPTP. Overexpression of NDI1 through stereotactic administration of a viral vector harboring the NDI1 gene into the substantia nigra protected mice from both the neurochemical and behavioral deficits elicited by MPTP. These data identify inhibition of complex I as a requirement for dopaminergic neurodegeneration and subsequent behavioral deficits produced by MPTP. Furthermore, combined with reports of a complex I defect in Parkinson's disease (PD) patients, the present study affirms the utility of MPTP in understanding the molecular mechanisms underlying dopaminergic neurodegeneration in PD.

PubMed ID: 17038483 Exiting the NIEHS site

MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects*; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism; Animals; Behavior, Animal; Brain/drug effects; Brain/metabolism; Brain/pathology; Cell Death/drug effects; Cell Line, Tumor; Dependovirus/genetics; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins/genetics; Dopamine Plasma Membrane Transport Proteins/metabolism; Dopamine/metabolism*; Electron Transport Complex I/antagonists & inhibitors*; Electron Transport Complex I/metabolism; Genetic Therapy; Genetic Vectors; Humans; MPTP Poisoning/chemically induced; MPTP Poisoning/metabolism*; MPTP Poisoning/pathology; MPTP Poisoning/prevention & control; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia/drug effects; Microglia/metabolism; Motor Activity/drug effects; Motor Skills Disorders/chemically induced; Motor Skills Disorders/metabolism*; Motor Skills Disorders/pathology; Motor Skills Disorders/prevention & control; NADH Dehydrogenase/biosynthesis*; NADH Dehydrogenase/genetics; Neuroglia/drug effects; Neuroglia/metabolism; Neurons/drug effects; Neurons/metabolism; Saccharomyces cerevisiae Proteins/biosynthesis*; Saccharomyces cerevisiae Proteins/genetics; Transfection

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