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 that environmental factors play an important role in typical, non-familial Parkinson's disease (PD), beginning after age 50. Epidemiological risk factor analyses of typical PD cases have identified several neurotoxicants, including MPP(+) (the active metabolite of MPTP), paraquat, dieldrin, manganese and salsolinol. Here, we tested the hypothesis that these neurotoxic agents might induce cell death in our nigral dopaminergic cell line, SN4741 (Son et al. 1999) through a common molecular mechanism. Our initial experiments revealed that treatment with both MPP(+) and the other PD-related neurotoxicants induced apoptotic cell death in SN4741 cells, following initial increases of H(2)O(2)-related ROS activity and subsequent activation of JNK1/2 MAP kinases. Moreover, we have demonstrated that during dopaminergic cell death cascades, MPP(+), the neurotoxicants and an oxidant, H(2)O(2) equally induce the ROS-dependent events. Remarkably, the oxidant treatment alone induced similar sequential molecular events: ROS increase, activation of JNK MAP kinases, activation of the PITSLRE kinase, p110, by both Caspase-1 and Caspase-3-like activities 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 dopaminergic cell death. Finally, the high throughput cDNA microarray screening using the current model identified downstream response genes, such as heme oxygenase-1, a constituent of Lewy bodies, that can be the useful biomarkers to monitor the pathological conditions of dopaminergic neurons under neurotoxic insult.
Chun
H S
HS
Department of Neurology and Neuroscience, Weill Medical College of Cornell University at The W.M. Burke Medical Research Institute, New York, USA.
Gibson
G E
GE
DeGiorgio
L A
LA
Zhang
H
H
Kidd
V J
VJ
Son
J H
JH
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007928:Lethal Dose 50; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D016877:Oxidants / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000209:etiology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D009498:Neurotoxins; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9; D017346:Protein Serine-Threonine Kinases; C501852:Cdk11b protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine