Статья

Mechanism of Toxicity in Rotenone Models of Parkinson's Disease

Todd ShererCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaRanjita BetarbetCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaClaudia TestaCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaByoung Boo SeoChosun UniversityJason R. RichardsonCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaJin Ho KimCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaGary W. MillerCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaTakao YagiCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaAkemi Matsuno‐YagiCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South KoreaJ. Timothy GreenamyreCenter for Neurodegenerative Disease, Departments of Neurology and Pharmacology, and Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, and Department of Neurology, Chosun University Medical College, Kwangju City, 501-717 South Korea

2003en

ABI

Аннотация

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and alpha-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 microm) 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 alpha-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.

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Идентификаторы

DOI: 10.1523/jneurosci.23-34-10756.2003

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