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

摘要: Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson9s disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation ubiquitin- α-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms rotenone-induced cell death, we developed a chronic vitro model based on treating human neuroblastoma cells with 5 nm for 1–4 weeks. For up to 4 weeks, grown the presence had normal morphology growth kinetics, but at this time point, ∼5% began undergo apoptosis. Short-term treatment (1 week) elevated soluble α-synuclein protein levels without changing message levels, suggesting that degradation was retarded. (4 weeks) increased SDS-insoluble ubiquitin. After latency >2 rotenone-treated showed evidence oxidative stress, loss glutathione DNA damage. slight elevation basal apoptosis markedly sensitized further challenge. In response H 2 O , there cytochrome c release from mitochondria, caspase-3 activation, apoptosis, all which occurred earlier much greater extent cells; caspase provided substantial protection. These studies indicate low-grade accumulation aggregation ubiquitin, progressive damage, caspase-dependent may be central PD pathogenesis.