Activation of c-Jun N-terminal protein kinase is a common mechanism underlying paraquat- and rotenone-induced dopaminergic cell apoptosis.
Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the substantia nigra of the brain. Although the underlying causes are not well characterized, epidemiological studies suggest an elevated risk of PD with occupational pesticide exposure. Here, we utilized pheochromocytoma (PC) 12 and SH-SY5Y cells as well as rat primary cultured dopaminergic neurons to investigate mechanisms for dopaminergic cell death induced by paraquat and rotenone, pesticides that are used to model PD in rodents. Both paraquat and rotenone induce selective loss of dopaminergic neurons in primary cultures. We discovered that paraquat induces apoptosis in PC12 cells but not in SH-SY5Y cells, while rotenone exposure causes apoptosis in SH-SY5Y cells but not in PC12 cells. The selective ability of paraquat and rotenone to induce apoptosis in different cell lines correlates with their ability to activate c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinases. Furthermore, JNK and p38 are required for rotenone-induced apoptosis in SH-SY5Y cells (K. Newhouse et al., 2004, Toxicol. Sci. 79, 137-146) as well as primary neurons, and for paraquat-induced apoptosis in PC12 cells. However, JNK but not p38 plays a role in paraquat-induced loss of primary cultured dopaminergic neurons. Our data identify JNK activation as a common mechanism underlying dopaminergic cell death induced by both paraquat and rotenone in model cell lines and primary cultures.
Klintworth
Heather
H
Toxicology Program in the Department of Environmental & Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234, USA.
Newhouse
Kathleen
K
Li
Tingting
T
Choi
Won-Seok
WS
Faigle
Roland
R
Xia
Zhengui
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008636:Mesencephalon / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D010269:Paraquat / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D010575:Pesticides; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010269:Paraquat; D004298:Dopamine