Parkinson's disease (PD) is the second most common aging-related neurodegenerative disorder. It is characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. Despite intense research in the past decade, mechanisms underlying the selective dopaminergic neuron death have not been well defined. Although inhibition of complex I activity is one of the leading hypotheses for dopaminergic neuron death associated with PD, this hypothesis has not been tested genetically. Our collaborator, Dr. Richard Palmiter, recently generated a transgenic mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Our preliminary data demonstrate that deletion of the Ndufs4 gene abolishes complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice. However, dopaminergic neurons in these cultures appeared normal and healthy with no decrease in survival during culture compared to neurons from wild-type mice. In this proposal, we will use conditional Ndufs4 knock out mice to determine if complex I inhibition is a main mechanism underlying dopaminergic neuron degeneration induced by the MPTP and rotenone models of PD in vivo and to elucidate complex I inhibition-independent mechanisms of cell death.

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Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in several models of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Lawler, Cindy P
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University of Washington
Public Health & Prev Medicine
Schools of Public Health
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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
Cai, Beibei; Xia, Zhengui (2008) p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription. Apoptosis 13:803-10
Wang, Yupeng; Liu, Lidong; Xia, Zhengui (2007) Brain-derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte-enhancer factor 2C through an ERK1/2-RSK2 signaling cascade. J Neurochem 102:957-66

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