Center for Gene-Environment Studies in Parkinson's Disease

University of California – Los Angeles

Marie-Françoise Chesselet, M.D., Ph.D.
mchesselet@mednet.ucla.edu
http://www.bri.ucla.edu/bri_research/parkinson_program.asp
http://www.bri.ucla.edu/

Project Description

The UCLA-CGEP will explore mechanisms by which genetic and environmental influences combine to increase the risk for Parkinson's disease (PD) in susceptible individuals through interplay between neurotoxic pesticides and biologic mechanisms regulating the neurotransmitter dopamine in brain cells. Parkinson's disease symptoms are caused by the death of dopamine producing cells and a lack of this neurotransmitter in the brain. There is extensive evidence that pesticides, a suspected risk factor for Parkinson's Disease , interact with multiple mechanisms that regulate the intra- and extracellular levels of the dopamine, which itself is a powerful oxidant that can be highly toxic to cells. Critical factors in this interaction of dopamine homeostasis and pesticides may be oxidative stress and the function of the proteasome, an organelle involved in protein degradation in cells. Both dopamine and pesticides can produce oxidative stress; pesticides can directly affect dopamine transporters, thus causing alterations in dopamine homeostasis, and possibly interfere with proteasomal function.

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Project 1: Environmental toxins and genes that influence cytosolic dopamine

Principal Investigator:  Beate Ritz, M.D., Ph.D.
britz@ucla.edu

Will use a high throughput genetic approach coupled with cellular assays to assess gene function and address the question of how and whether genetic variations impact dopamine homeostasis in humans that participate in a large epidemiologic study at UCLA. This project will also use the model organism Drosophila melanogaster (the fruit fly) to study gene-environment interactions relevant to dopamine metabolism. We will use the power of fly genetics to identify new genes that may contribute to neuroprotective mechanisms relevant to both environmental toxins and dopamine itself.

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Project 2: Interaction between pesticides and genetic alterations of dopamine homeostasis in mice

Principal Investigator: Marie-Françoise Chesselet, M.D., Ph.D.
mchesselet@mednet.ucla.edu

Will employ the extensive mouse colonies at UCLA, specifically mice with genetic alterations in the vesicular and cytoplasmic dopamine transporters as well as in proteins known to cause familial Parkinson's disease. Exposing these mice to certain pesticides, we will examine whether variations in dopamine homeostasis due to genetic factors will increase the ability of pesticides to cause oxidative stress in dopamine-producing neurons and whether this interaction increases the vulnerability of dopamine neurons in vivo.

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Project 3: Pesticides and proteosomal dysfunction: Genetic susceptibility in cellular models

Principal Investigator: Jeff Bronstein, M.D., Ph.D.
jbronste@ucla.edu

One key player in the vulnerability of dopamine neurons in Parkinson's Disease is the proteasomal pathway; i.e. growing evidence suggests that proteosomal dysfunction plays a critical role in neurodegenerative diseases. Thus, project III will use immortalized cell lines, primary cell cultures from the genetically engineered mice used in project II, and lymphoblasts from patients identified from the epidemiologic study to examine the effects of pesticides on the function of the proteasome.

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