Dopaminergic cell death induced by MPP+, oxidant and specific neurotoxicants shares the common molecular mechanism

Recent etiological study in twins (Tanner et al. 1999) strongly suggests th at environmental factors play an important role in typical, non-familial Pa rkinson's disease (PD), beginning after age 50. Epidemiological risk factor analyses of typical PD cases have identified several neurotoxicants, inclu ding MPP+ (the active metabolite of MPTP), paraquat, dieldrin, manganese an d salsolinol. Here, we tested the hypothesis that these neurotoxic agents m ight induce cell death in our nigral dopaminergic cell line, SN4741 (Son et al 1999) through a common molecular mechanism. Our initial experiments rev ealed that treatment with both MPP+ and the other PD-related neurotoxicants induced apoptotic cell death in SN4741 cells, following initial increases of H2O2-related ROS activity and subsequent activation of JNK1/2 MAP kinase s. Moreover, we have demonstrated that during dopaminergic cell death casca des, MPP+, the neurotoxicants and an oxidant, H2O2 equally induce the ROS-d ependent events. Remarkably, the oxidant treatment alone induced similar se quential molecular events: ROS increase, activation of JNK MAP kinases, act ivation of the PITSLRE kinase, p110, by both Caspase-1 and Caspase-8-like a ctivities and apoptotic cell death. Pharmacological intervention using the combination of the antioxidant Trolox and a pan-caspase inhibitor Boc-(Asp) -fmk (BAF) exerted significant neuroprotection against ROS-induced dopamine rgic cell death. Finally, the high throughput cDNA microarray screening usi ng the current model identified downstream response genes, such as heme oxy genase-1, a constituent of Lewy bodies, that can be the useful biomarkers t o monitor the pathological conditions of dopaminergic neurons under neuroto xic insult.