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The Journal of Neuroscience, November 26, 2003, 23(34):10756-10764
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Cellular/Molecular
Mechanism of Toxicity in Rotenone Models of Parkinson's Disease
Todd B. Sherer,1,2 Ranjita Betarbet,1,2 Claudia M. Testa,1,2 Byoung Boo Seo,5 Jason R. Richardson,1,4 Jin Ho Kim,6 Gary W. Miller,1,4 Takao Yagi,5 Akemi Matsuno-Yagi,5 andJ. Timothy Greenamyre1,2,3 1Center for Neurodegenerative Disease, Departments of 2Neurology and 3Pharmacology, and 4Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, 5Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and 6Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South Korea
Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and
-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nM to 1 µM) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase of Saccharomyces cerevisiae (NDI1), which incorporates into the mammalian ETC and acts as a "replacement" for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by
Key words: mitochondria; oxidative stress; NADH dehydrogenase; dopamine; organotypic;
Received Aug 11, 2003; revised September 30, 2003; accepted October 1, 2003.
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