The Center for Gene-Environment Studies in Parkinson’s Disease at UCLA (UCLA-CGEP) bridges three major NIH and VA-supported awards in Parkinson’s disease (PD) and one NH-sponsored study of Huntington’s disease. The central hypothesis of the UCLA-CGEP is that gene and environment toxins combine to increase the risk for PD in susceptible individuals through interplay between pesticides and mechanisms regulating dopamine homeostasis. Critical factors in this interaction are oxidative stress and resulting alterations in proteasomal function.

Project I, “Environmental Toxins and Genes that Influence Dopamine in Drosophila and Humans,” examines inter-individual variability of dopamine vesicular transporter (VMAT) expression due to promotor variants in two human populations in parallel with a reporter gene assay. These populations are genotyped for functional VMAT2 variants and association analyses of gene-environment interactions and pesticide exposures collected in the parent grant. In addition, Drosophila genetics are used to determine how the expression of VMAT affects dopamine-mediated toxicity and to identify genes that modulate VMAT function, which are then examined in the human population for their relevance to increased risk of PD.

Project II, “Interaction Between Pesticides and Genetic Alterations in Dopamine Homeostasis in Mice,” tests the hypothesis that pesticides and genetic variations in combination increase the vulnerability of dopaminergic neurons, and that one of the mechanisms involved is oxidative stress. Genetically engineered mice with a reduction in expression of VMAT or the cytoplasmic dopamine transporters, and mice with altered expression of alpha-synuclein and parkin, two proteins known to cause familial PD, are examined. Behavior and quantitative anatomy are used to assess the effect of pesticides on dopaminergic neurons in these genetically altered mice. Histology, gene expression profiling, in vivo neurochemistry and slice electrophysiology are used to examine the role of oxidative stress in this interaction.

Project III, “Pesticides and Proteasomal Dysfunction: Genetic Susceptibility in Cellular Models,” test the hypothesis that proteasomal dysfunction is central to the deleterious effects of the combined environmental and genetic insults. Cell lines, primary neuronal cultures from genetically altered mice, and human lymphoblasts are examined.