JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death.
Mechanistic studies underlying dopaminergic neuron death may identify new drug targets for the treatment of Parkinson disease. Epidemiological studies have linked pesticide exposure to increased risk for sporadic Parkinson disease. Here, we investigated the role of c-Jun-N-terminal kinase 3 (JNK3), a neural-specific JNK isoform, in dopaminergic neuron death induced by the pesticides rotenone and paraquat. The role of JNK3 was evaluated using RNA silencing and gene deletion to block JNK3 signaling. Using an antibody that recognizes all isoforms of activated JNKs, we found that paraquat and rotenone stimulate JNK phosphorylation in primary cultured dopaminergic neurons. In cultured neurons transfected with Jnk3-specific siRNA and in neurons from Jnk3 mice, JNK phosphorylation was nearly abolished, suggesting that JNK3 is the main JNK isoform activated in dopaminergic neurons by these pesticides. Paraquat- and rotenone-induced death of dopaminergic neurons was also significantly reduced by Jnk3 siRNA or Jnk3 gene deletion, and deletion of the Jnk3 gene completely attenuated paraquat-induced dopaminergic neuron death and motor deficits in vivo. Our data identify JNK3 as a common and critical mediator of dopaminergic neuron death induced by paraquat and rotenone, suggesting that it is a potential drug target for Parkinson disease treatment.
Choi
Won-Seok
WS
Toxicology Program in the Department of Environmental and Occupational Health Sciences, Graduate Program in Neurobiology and Behavior, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
Abel
Glen
G
Klintworth
Heather
H
Flavell
Richard A
RA
Xia
Zhengui
Z
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D017353:Gene Deletion; D006540:Herbicides / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000235:genetics; D010269:Paraquat / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D006540:Herbicides; D007306:Insecticides; D034741:RNA, Small Interfering; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D048057:Mitogen-Activated Protein Kinase 10; D053148:Caspase 3; D010269:Paraquat; D004298:Dopamine