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Your Environment. Your Health.

University of California, Los Angeles

Center for Gene-Environment in Parkinson’s Disease



Marie-Francoise Chesselet, M.D., Ph.D., Beate Ritz
mchesselet@mednet.ucla.edu;britz@ucla.edu

Project Description:

The UCLA Center for Gene Environment in Parkinson’s Disease investigates how exposure to agricultural pesticides can lead to Parkinson’s disease in humans. Center researchers study pesticide exposure and Parkinson’s disease risk in people living in the California Central Valley. Other studies use animal models and cell cultures to better understand how pesticides affect cellular processes potentially involved in Parkinson’s disease.

 

Results from studies at this center could lead to the development of new targets for therapies that stop or reverse the course of the disease. In addition, a better understanding of the neurotoxicity of widely used pesticides will help in the development of strategies that can protect people exposed to these pesticides.


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Project Highlights

Chesselet took questions at a gathering of NIEHS Centers for Neurodegeneration Science grantees

Chesselet took questions at a gathering of NIEHS Centers for Neurodegeneration Science grantees.

(Photo courtesy of Steve McCaw)

Ritz’s team created maps that show areas of pesticide application around a town

Ritz’s team created maps that show areas of pesticide application around a town (red equals higher poundage per acre than pink). (Images courtesy of Beate Ritz)

Project 1: Cellular studies 

Project leader: Jeff Bronstein, M.D., Ph.D.

jbronste@ucla.edu

 

Parkinson’s disease is associated with the loss of neurons that produce the  neurotransmitter dopamine in the substantia nigra area of the brain. Researchers involved in this project use cultured cells to study how pesticides disrupt cell processes that make dopamine-secreting neurons vulnerable. These studies are revealing how contaminants increase Parkinson’s disease risk and are identifying genetic features to study in Project 4.

 

Project 2: Genetic studies in flies 

Project leader: David Krantz, M.D., Ph.D.

dkrantz@ucla.edu

 

This project uses fruit flies as a model to study how pesticides increase Parkinson’s disease risk. The researchers are examining how pesticides, both alone and combined with gene mutations, lead to the death of neurons that produce dopamine. Other center projects use results from this project to develop rodent models and to determine biochemical pathways for study in humans. New fly models from this project will also allow the researchers to evaluate potential strategies for protecting neurons from the effects of pesticides.

 

Project 3: In vivo studies in rodents 

Project leader: Marie-Francoise Chesselet, M.D., Ph.D.

mchesselet@mednet.ucla.edu  

 

Researchers involved in this project use rodent models to study cellular processes affected by pesticides. They are identifying genes involved in those processes and working to better understand how pesticides damage neurons that secrete dopamine. This project is linking the mechanisms identified in the center’s cell and fly studies with the toxicity of compounds that increase human Parkinson’s disease risk in Project 4.

 

Project 4: Studies in humans 

Project leader: Beate Ritz, M.D., Ph.D.

britz@ucla.edu  

 

Using data from the Parkinson Environment Gene (PEG) study, researchers are testing the association of genes and pesticides with Parkinson’s disease. The PEG study combines exceptional pesticide exposure data with a well-characterized group of Parkinson’s disease patients and controls. The investigators examine how gene variants identified in other center projects interact with pesticides and/or other genes to increase Parkinson’s disease risk in humans. They are also replicating earlier studies using new groups of patients. The findings from this project are creating hypotheses to test in the other projects.

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Research Papers:

  • Lee P-C, Bordelon Y, Bronstein J, Ritz B. In press. Traumatic Brain Injury, Paraquat Exposure and their Relationship to Parkinson Disease. Neurology.
  • Ritz B, Rhodes SL, Bordelon Y, Bronstein J. 2012. α-Synuclein Genetic Variants Predict Faster Motor Symptom Progression in Idiopathic Parkinson Disease. PLoS One 7(5):e36199. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/22615757) ]
  • Prabhudesai S, Sinha S, Attar A, Kotagiri A, Fitzmaurice AG, Lakshmanan R, Ivanova MI, Loo JA, Klärner FG, Schrader T, Stahl M, Bitan G, Bronstein JM. 2012. A novel "molecular tweezer" inhibitor of alpha-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics 9(2): 464-476. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/22373667) ]
  • Wang A, Costello S, Cockburn M, Zhang X, Bronstein J, Ritz B. 2011. Parkinson's disease risk from ambient exposure to pesticides. Eur J Epidemiol 26(7):547-555. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21505849) ]
  • Hutson CB, Lazo CR, Mortazavi F, Giza CC, Hovda D, Chesselet MF. 2011. Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat. J Neurotrauma. 28(9):1783-1801. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21644813) ]
  • Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F, Magen I, Cepeda C, Ackerson LC, Walwyn W, Masliah E, Chesselet MF, Levine MS, Maidment NT. 2011. Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human a-synuclein. J Neurosci Res. 89(7):1091-1102. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21488084) ]
  • Lawal HO, Chang HY, Terrell AN, Brooks ES, Pulido D, Simon AF, Krantz DE. 2010. The Drosophila vesicular monoamine transporter reduces pesticide-induced loss of dopaminergic neurons. Neurobiol Dis. 40(1):102-12. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20472063) ]
  • Gatto NM, Rhodes SL, Manthripragada AD, Bronstein J, Cockburn M, Farrer M, Ritz B. 2010. a-Synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease. Neuroepidemiology 35(3):191-195. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20664293) ]
  • Manthripragada AD, Costello S, Cockburn MG, Bronstein JM, Ritz B. 2010. Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease. Epidemiology 21(1):87-94. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19907334) ]
  • Gatto NM, Cockburn M, Bronstein J, Manthripragada AD, Ritz B. 2009. Well-Water Consumption and Parkinson’s Disease in Rural California. Environ Health Perspect 117:1912-1918. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20049211) ]
  • Ritz BR, Manthripragada AD, Costello S, Lincoln SJ, Farrer MJ, Cockburn M, Bronstein J. 2009. Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease. Environ Health Perspect 117:964-969. [Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19590691) ]


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