Although the etiology of Parkinson's disease (PD) has not been defined, epidemiological studies have indicated a correlation between increased risk for PD and occupational exposure to pesticides including paraquat, a widely used herbicide. Interestingly, treatment of mice with paraquat produces many key features of PD including dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc) of the brain and formation of 1-synuclein containing inclusion bodies. Therefore, studies of paraquat-induced dopaminergic neuron death may provide important new information concerning mechanisms governing the death and survival of dopaminergic neurons and thereby provide important new insights concerning the molecular basis of PD. Recently, we discovered that paraquat selectively kills dopaminergic neurons in primary cultures by a mechanism that requires activation of the c-Jun NH2-terminal protein kinase (JNK) and JNK-induced gene expression. Furthermore, paraquat-induced dopaminergic neuron death is inhibited by bFGF. This proposal is based upon the hypothesis that JNK, specifically the neurospecific JNK3 isoform, plays an important role in paraquat-induced death of dopaminergic neurons, and that this cell death may be mediated by BimEL and antagonized by bFGF. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of PD. Furthermore, our proposed research meets the goals of NIEHS strategic plan, especially to "support research that improves our understanding of signal transduction pathways and their influence on disease" under goal #2, which is to "use environmental toxicants to understand basic mechanisms in human biology".
Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying paraquat-induced dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.
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