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ToxSci Advance Access published online on October 12, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl133
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 25, 2006
Accepted October 7, 2006

Neurotoxicology

Obligatory Role for Complex I Inhibition in the Dopaminergic Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Jason R. Richardson 1, W. Michael Caudle 2, Thomas S. Guillot 2, Jodi L. Watson 2, Eiko Nakamaru-Ogiso 3, Byoung Boo Seo 3, Todd B. Sherer 4, J. Timothy Greenamyre 5, Takao Yagi 3, Akemi Matsuno-Yagi 3, and Gary. W. Miller 2 *

1 Department of Environmental and Occupational Medicine, University of Medicine and Dentistry-New Jersey/Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854; Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322
2 Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322
3 Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
4 Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Present address: The Michael J. Fox Foundation for Parkinson's Disease Research, New York, NY 10163
5 Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322; Department of Neurology and Pittsburgh Institute for Neurodegenerative Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261

* To whom correspondence should be addressed.
Gary. W. Miller, E-mail: gary.miller{at}emory.edu


  Abstract

Administration of MPTP to mice and non-human 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 NADH 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 over-expression abolished the toxicity of MPP+, the active metabolite of MPTP. Over-expression 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 PD patients, the present study affirms the utility of MPTP in understanding the molecular mechanisms underlying dopaminergic neurodegeneration in Parkinson's disease.

Keywords: mitochondria; complex I; MPTP; Parkinson's disease; dopamine transporter; viral expression.
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