Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
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.
Richardson
Jason R
JR
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, USA.
Caudle
W Michael
WM
Guillot
Thomas S
TS
Watson
Jodi L
JL
Nakamaru-Ogiso
Eiko
E
Seo
Byoung Boo
BB
Sherer
Todd B
TB
Greenamyre
J Timothy
JT
Yagi
Takao
T
Matsuno-Yagi
Akemi
A
Miller
Gary W
GW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D019957:Motor Skills Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009245:NADH Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
D050483:Dopamine Plasma Membrane Transport Proteins; C493237:Ndi1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; D004298:Dopamine