Environmental toxicants including pesticides may contribute to the development of various neurodegenerative disorders including Parkinson's disease (PD). One of the mechanisms implicated in various neurodegeneration is neuronal apoptosis. We discovered that chlorpyrifos and rotenone both stimulate apoptosis in neuronal cells, suggesting that pesticide-induced apoptosis may play a role in neurodegeneration. Consequently, it is important to elucidate molecular mechanisms for induction of apoptosis by pesticides in neurons. The overall objective of this project is to elucidate apoptotic mechanisms for chlorpyrifos- and rotenone-induced apoptosis in neurons. Chlorpyrifos, an organophosphate pesticide, is one of the most commonly used pesticides. Its primary target of toxicity is the CNS. Treatment of rats with rotenone, a common insecticide, causes all PD symptoms. Therefore, chlorpyrifos and rotenone, two distinct classes of pesticides, are chosen as models to study pesticide-induced neuronal apoptosis. Our preliminary data suggest that both chlorpyrifos and rotenone induce apoptosis in primary cultured cortical neurons and SH-SY5Y cells. They also activate the stress-activated MAP kinases, JNK and p38. We hypothesize that activation of these kinases is important for chlorpyrifos- and rotenone-induced apoptosis in neurons. We will test this hypothesis and elucidate downstream mechanisms by which chlorpyrifos and rotenone stimulation of JNK and p38 causes neuronal apoptosis. This study should provide valuable new information concerning the molecular basis of pesticide-induced apoptosis in neurons and new insights concerning the role of environmental toxicants in neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012215-04
Application #
7172314
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Lawler, Cindy P
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2007-02-01
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$307,254
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Choi, Won-Seok; Kim, Hyung-Wook; Tronche, François et al. (2017) Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson's disease-like non-motor symptoms without loss of dopamine neurons. Sci Rep 7:44989
Kim, Hyung-Wook; Choi, Won-Seok; Sorscher, Noah et al. (2015) Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo. Neurobiol Aging 36:2617-27
Choi, Won-Seok; Kim, Hyung-Wook; Xia, Zhengui (2015) JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death. Toxicology 328:75-81
Choi, Won-Seok; Xia, Zhengui (2014) Maneb-induced dopaminergic neuronal death is not affected by loss of mitochondrial complex I activity: results from primary mesencephalic dopaminergic neurons cultured from individual Ndufs4+/+ and Ndufs4-/- mouse embryos. Neuroreport 25:1350-5
Choi, Won-Seok; Kim, Hyung-Wook; Xia, Zhengui (2013) Preparation of primary cultured dopaminergic neurons from mouse brain. Methods Mol Biol 1018:61-9
Choi, Won-Seok; Palmiter, Richard D; Xia, Zhengui (2011) Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model. J Cell Biol 192:873-82
Choi, Won-Seok; Klintworth, Heather M; Xia, Zhengui (2011) JNK3-mediated apoptotic cell death in primary dopaminergic neurons. Methods Mol Biol 758:279-92
Choi, Won-Seok; Abel, Glen; Klintworth, Heather et al. (2010) JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death. J Neuropathol Exp Neurol 69:511-20
Klintworth, Heather; Garden, Gwenn; Xia, Zhengui (2009) Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neurosci Lett 462:1-5
Choi, Won-Seok; Kruse, Shane E; Palmiter, Richard D et al. (2008) Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. Proc Natl Acad Sci U S A 105:15136-41

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