In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease.
Recent studies suggest that dysfunction of the NADH-quinone oxidoreductase (complex I) is associated with a number of human diseases, including neurodegenerative disorders such as Parkinson disease. We have shown previously that the single subunit rotenone-insensitive NADH-quinone oxidoreductase (Ndi1) of Saccharomyces cerevisiae mitochondria can restore NADH oxidation in complex I-deficient mammalian cells. The Ndi1 enzyme is insensitive to complex I inhibitors such as rotenone and 1-methyl-4-phenylpyridinium ion, known as a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test the possible use of the NDI1 gene as a therapeutic agent in vivo, we chose a mouse model of Parkinson disease. The NDI1-recombinant adeno-associated virus particles (rAAV-NDI1) were injected unilaterally into the substantia nigra of mice. The animals were then subjected to treatment with MPTP. The degree of neurodegeneration in the nigrostriatal system was assessed immunohistochemically through the analysis of tyrosine hydroxylase and glial fibrillary acidic protein. It was evident that the substantia nigra neurons on the side used for injection of rAAV-NDI1 retained a high level of tyrosine hydroxylase-positive cells, and the ipsilateral striatum exhibited significantly less denervation than the contralateral striatum. Furthermore, striatal concentrations of dopamine and its metabolites in the hemisphere that received rAAV-NDI1 were substantially higher than those of the untreated hemisphere, reaching more than 50% of the normal levels. These results indicate that the expressed Ndi1 protein elicits resistance to MPTP-induced neuronal injury. The present study is the first successful demonstration of complementation of complex I by the Ndi1 enzyme in animals.
Seo
Byoung Boo
BB
Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Nakamaru-Ogiso
Eiko
E
Flotte
Terence R
TR
Matsuno-Yagi
Akemi
A
Yagi
Takao
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D009245:NADH Dehydrogenase / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D012402:Rotenone / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
D005904:Glial Fibrillary Acidic Protein; C493237:Ndi1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I