In vivo complementation of complex I by the yeast Ndi1 enzyme: possible application for treatment of Parkinson's disease
Seo BB, Nakamaru-Ogiso E, Flotte TR, Matsuno-Yagi A, Yagi T
Journal of Biological Chemistry (2006)
Category: mitochondrial diseases, Parkinson disease, respiration, complex I ¤ Added: Mar 20, 2006 ¤ Rating: ◊◊
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’s disease (PD). We have previously shown 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 PD. The NDI1-recombinant adeno-associated virus particles (rAAV-NDI1) were injected unilaterally into the substantia nigra (SN) 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 (TH) and glial fibrillary acidic protein (GFAP). It was evident that the SN neurons on the side used for injection of rAAV-NDI1 retained a high level of TH-positive cells and that 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.