? ? Parkinson's Disease (PD) is a disabling neurodegenerative disease currently affecting more than 1.5 million people in the United States. While the etiology of PD is not completely known, it is believed that environmental factors play a major role in development of disease. Pesticide exposure is one of the few risk factors identified for PD by epidemiological studies. Research performed in the investigators' laboratories and others have determined that mitochondrial complex I and the vesicular monoamine transporter 2 (VMAT2) are targets of pesticides implicated in PD (e.g. rotenone, pyrethroids, and organochlorines) and that oxidative stress is a key mechanism of toxicity of these compounds. However, previous studies have focused primarily on a small number of pesticides. With this in mind, the investigators have developed a novel assay for rapidly screening pesticides for their ability to inhibit the binding of 3H-dihydrorotenone to complex I in isolated mitochondria and are developing rapid screens for identifying compounds that inhibit VMAT2 and cause oxidative damage. They have used these methods to screen a number of known complex I inhibitors and have identified the pesticide pyridaben as the most potent in generating oxidative stress and damaging cells. Because of the sheer number of pesticides and other environmental contaminants that may be involved in etiology of PD, it is important to develop a rapid screening paradigm to identify the toxicants most likely to damage the dopaminergic system. Here the investigators propose to build upon their experience with pesticides known to inhibit complex I to screen a number of pyrethroid and organochlorine pesticides for their ability to inhibit complex I and VMAT2, and generate oxidative damage. Data obtained from the in vitro screening phase will then be used to select the most likely candidates to damage the dopaminergic system and be tested for their ability to induce parkinsonism in mice. ? ? ?
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