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

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*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, New Jersey 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

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†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

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†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

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†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

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§Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

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§Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

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†Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322

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Present address: The Michael J. Fox Foundation for Parkinson's Disease Research, New York, NY 10163.

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†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, Pennsylvania 15261

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§Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

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§Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

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Accepted:

07 October 2006

Published:

12 October 2006

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Jason R. Richardson, W. Michael Caudle, Thomas S. Guillot, Jodi L. Watson, Eiko Nakamaru-Ogiso, Byoung Boo Seo, Todd B. Sherer, J. Timothy Greenamyre, Takao Yagi, Akemi Matsuno-Yagi, Gary W. Miller, Obligatory Role for Complex I Inhibition in the Dopaminergic Neurotoxicity of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), Toxicological Sciences, Volume 95, Issue 1, January 2007, Pages 196–204, https://doi.org/10.1093/toxsci/kfl133
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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.

© 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

Topic:

• dopamine
• cell culture techniques
• mitochondria
• neurotoxicity syndromes
• 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• nerve degeneration
• rotenone
• mice
• toxic effect

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