The major theme of the UCLA CENTER FOR GENE ENVIRONMENT IN PARKINSON DISEASE (PD) is to identify novel mechanisms of pathogenesis for sporadic PD by understanding the primary cellular mechanisms by which agricultural pesticides that we and others have demonstrated to be risk factors for PD. produce dysfunction and death of dopamine neurons in cellular and animal models, and lead to PD in humans. Our group has begun to identify an association between exposure to specific pesticides and an increased risk for PD in an exceptionally well-characterized patient cohort in the agricultural region of California Central Valley. In parallel experiments, we have discovered that several of these pesticides affect specific cellular pathways potentially involved in PD. In particular, we have evidence that several agricultural pesticides associated with an increased risk of PD interfere with the ubiquitin-proteasome system (UPS). In addition to their effects on the proteasome, these pesticides to varying extent interfere with microtubule assembly, and/or inhibit aldehyde dehydrogenase, a key detoxification enzyme. The central hypothesis to be tested in the Center is that disruption of these particular cellular mechanisms by some agricultural pesticides is responsible for their ability to increase the risk of PD. Four integrated projects will combine human-based studies in a unique epidemiological cohort (project 4) with basic research studies in cellular (project 1), Drosophila (project 2) and rodent (project 3) models. We expect that the results of our studies will identify novel molecular pathways involved in neurodegeneration in PD, and specific therapeutic targets to stop or reverse the course of the disease. In addition, a better understanding of the potential neurotoxicity of widely used pesticides will have implications for their use in the environment to protect the health of workers and the general population, who are exposed to environmental pesticides in or near agricultural settings.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Program Projects (P01)
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Special Emphasis Panel (ZES1-LWJ-G (CN))
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Lawler, Cindy P
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Lee, P C; Bordelon, Y; Bronstein, J et al. (2015) Head injury, ?-synuclein genetic variability and Parkinson's disease. Eur J Neurol 22:874-8
Roy, Bidisha; Jackson, George R (2014) Interactions between Tau and ?-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease. Hum Mol Genet 23:3008-23
Subramaniam, Sudhakar Raja; Vergnes, Laurent; Franich, Nicholas R et al. (2014) Region specific mitochondrial impairment in mice with widespread overexpression of alpha-synuclein. Neurobiol Dis 70:204-13
Reddy, India A; Stanwood, Gregg D; Galli, Aurelio (2014) Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward. Neurochem Int 73:49-55
Liew, Zeyan; Wang, Anthony; Bronstein, Jeff et al. (2014) Job exposure matrix (JEM)-derived estimates of lifetime occupational pesticide exposure and the risk of Parkinson's disease. Arch Environ Occup Health 69:241-51
Martin, Ciara A; Krantz, David E (2014) Drosophila melanogaster as a genetic model system to study neurotransmitter transporters. Neurochem Int 73:71-88
Rhodes, Shannon L; Buchanan, Daniel D; Ahmed, Ismail et al. (2014) Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin. Neurobiol Dis 62:172-8
Wang, Anthony; Cockburn, Myles; Ly, Thomas T et al. (2014) The association between ambient exposure to organophosphates and Parkinson's disease risk. Occup Environ Med 71:275-81
Attar, Aida; Chan, Wai-Ting Coco; Klärner, Frank-Gerrit et al. (2014) Safety and pharmacological characterization of the molecular tweezer CLR01 - a broad-spectrum inhibitor of amyloid proteins' toxicity. BMC Pharmacol Toxicol 15:23
Bakhoum, Mathieu F; Bakhoum, Christine Y; Ding, Zhixia et al. (2014) Evidence for autophagic gridlock in aging and neurodegeneration. Transl Res 164:1-12

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