Although the cause(s) of Parkinson's disease (PD) is unknown at present, the pathogenesis of dopamine-producing cell death in PD is being intensively investigated. The data from these studies suggest that defects in mitochondrial complex I in dopamine-producing cells may be involved in PD. For example, administration of I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whose metabolite (1-methyl-4-phenylpyridinium ion, MPP') acts as a complex I inhibitor, causes Parkinsonism-like symptoms to primates and rodents. Recently, it was demonstrated that rotenone, which is a specific inhibitor for complex 1, induces Parkinsonian-like symptoms. In other studies, approximately 40% of PD patients show partial deficiency of complex I activity. Complex I capacity in dopamine-producing cells is reported to be considerably lower than that in liver and muscle. Therefore, it is conceivable that subtle dysfunction of complex I in the substantia nigra may induce PD. If so, in order to prevent the progress of PD, relieving dopaminergic cells of harmful effects caused by dysfunction of complex I may provide a novel remedy for PD. The applicants have shown that the rotenone-insensitive internal NADH dehydrogenase (Ndi 1) of Saccharomyces cerevisiae mitochondria restores respiratory function to complex I-deficient mammalian cells. The NDII-transduced cells were insensitive to rotenone and MPP'. It is proposed to investigate the potential of the Ndil protein to protect against neurodegeneration and its effectiveness in retarding PD. The studies during this grant period are as follows: (1) Use of NDII-recombinant adeno-associated virus as a remedy in rodent models of PD. (2) Effects of MPTP on transgenic mice expressing the Ndil enzyme in the dopamine-producing tissues.
| Sherer, Todd B; Betarbet, Ranjita; Testa, Claudia M et al. (2003) Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci 23:10756-64 |
| Seo, Byoung Boo; Nakamaru-Ogiso, Eiko; Flotte, Terence R et al. (2002) A single-subunit NADH-quinone oxidoreductase renders resistance to mammalian nerve cells against complex I inhibition. Mol Ther 6:336-41 |
