CGEP

UCLA Center For Gene Environment in Parkinson's disease
Funded by NIEHS

(COMPLETED 6/2014)
Director: Marie-Francoise Chesselet, M.D., Ph.D.

 

Co-Director: Beate Ritz, M.D., Ph.D.

 

Principal Investigators: Jeff Bronstein, David Krantz, Michael Levine

The UCLA CGEP continues to explore the environmental and genetic mechanisms that contribute to the risk for Parkinson’s disease, in order to understand the underlying mechanisms of disease, identify potential targets, and develop more effective treatments. Previous epidemiological studies at the CGEP have established that exposure to certain agricultural pesticides indeed increases the risk of developing Parkinson’s disease. In parallel, we have identified at the cellular level, specific pathways that are affected by a number of these pesticides.  In particular, studies at the CGEP are focused on the disruptions caused by these pesticides in the ubiquitin-proteasome system, as well as microtubule assembly and/or aldehyde dehydrogenase inhibition, involved in protein degradation, trafficking, and detoxification, all of which are also involved in the regulation of dopamine, the key neurotransmitter in Parkinson's disease.

Building upon a strong collaborative foundation, our team of neurologists, epidemiologists and basic scientists uses a multi-pronged approach to elucidate the mechanisms involved in the underlying pathology of PD. Studies at the CGEP combine four integrated projects using cellular models, rodents, drosophila, and human subjects.  Various cellular assays and cultures are used to determine which of the identified molecules and pathways are affected by pesticides, and how they might influence dopamine regulation and toxicity, leading to the increased vulnerability to dopaminergic neurons of the substantia nigra.  The results obtained from cellular models will be further assessed using drosophila and rodent models to precisely define the contribution of each pathway, and identify additional molecules involved in degeneration resulting from pesticide exposure.  Studies in a well-characterized patient population in the Central Valley of California will further determine whether variations in selected genes (based on the cellular and animal studies) interact with certain pesticides and/or other genes to modulate the risk of PD in humans. Any additional genes of interest obtained in the humans studies will be further evaluated for their role in the degenerative process in the cellular, rodent, and drosophila models.

The overarching goal of these studies is to understand the underlying cellular pathways and molecules which are affected by particular pesticides.  We expect that our results will ultimately present us with potential novel therapeutic targets to slow or even halt the progression of Parkinson's disease.  Furthermore,  a better understanding of possible neurotoxic effects of pesticides will have implications for their use in the environment, and protecting farm workers and the general population from excessive exposure.