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The Journal of Neuroscience, August 15, 2002, 22(16):7006-7015

An In Vitro Model of Parkinson's Disease: Linking Mitochondrial Impairment to Altered -Synuclein Metabolism and Oxidative Damage

Todd B. Sherer¹, Ranjita Betarbet¹, Amy K. Stout¹, Serena Lund¹, Melisa Baptista², Alexander V. Panov¹, Mark R. Cookson², and J. Timothy Greenamyre¹

¹ Center for Neurodegenerative Disease and Department of Neurology, Emory University, Atlanta, Georgia 30322, and ² National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892

Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and -synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nM rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, ~5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble -synuclein protein levels without changing message levels, suggesting that -synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble -synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H₂O₂, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of -synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.

Key words: -synuclein; cytochrome c; glutathione; caspase-3; carbonyls; ubiquitin

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22167006-10$05.00/0

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