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Obligatory role for complex i inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mptp)

Academic Article
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Overview

authors

  • Richardson, J. R.
  • Caudle, W. M.
  • Guillot, T. S.
  • Watson, J. L.
  • Nakamaru-Ogiso, E.
  • Seo, B. B.
  • Sherer, T. B.
  • Greenamyre, J. T.
  • Yagi, Takao
  • Matsuno-Yagi, A.
  • Miller, G. W.

publication date

  • January 2007

journal

  • Toxicological Sciences  Journal

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.

subject areas

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Behavior, Animal
  • Brain
  • Cell Death
  • Cell Line, Tumor
  • Dependovirus
  • Disease Models, Animal
  • Dopamine
  • Dopamine Plasma Membrane Transport Proteins
  • Electron Transport Complex I
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • MPTP Poisoning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia
  • Motor Activity
  • Motor Skills Disorders
  • NADH Dehydrogenase
  • Neuroglia
  • Neurons
  • Saccharomyces cerevisiae Proteins
  • Transfection
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Research

keywords

  • MPTP
  • Parkinson's disease
  • complex I
  • dopamine transporter
  • mitochondria
  • viral expression
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Identity

International Standard Serial Number (ISSN)

  • 1096-6080

Digital Object Identifier (DOI)

  • 10.1093/toxsci/kfl133

PubMed ID

  • 17038483
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Additional Document Info

start page

  • 196

end page

  • 204

volume

  • 95

issue

  • 1

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