Objective/Rationale:
The goals of the project are to identify a unique set of DNA modifications (methylation) in brain sections of those with and without Parkinson’s disease (PD), exposed to organochlorine and/or plantation work. Both exposures have been shown to be risk factors for PD in this Japanese male population. A secondary objective is to see if these same DNA modifications will be reflected in the subjects’ DNA isolated from blood collected at midlife prior to autopsy.
Project Description:
We will perform the DNA modification (epigenetic) tests in brain tissues and blood cells and compare PD samples to control samples. The differentially modified DNA regions in brains and blood will be mapped to genes and their exact functional gene locations. Significant epigenetic markers of PD or organochlorine/plantation work exposures from the brain tissue and blood will be categorized into concordant and discordant groups. Those in concordant groups can serve as possible disease biomarkers in blood, a more accessible tissue in living subjects. Differentially modified genes will be subjected to biological pathway analyses to identify mechanisms involved in PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Distinct DNA methylation profiles significantly correlated to PD and organochlorines and/or plantation work exposures, if found to occur both in the brain and peripheral blood, can be utilized as important biomarkers to predict disease or indicate past exposure to these risk factors in at-risk populations. These uniquely distinct methylation profiles can then be utilized to design novel drugs to turn key genes on and off to prevent or treat disease symptoms or outcomes.
Anticipated Outcome:
We expect to identify significant differences of DNA modifications (gene methylation patterns) correlated to organochlorine/plantation work exposure and Parkinson’s disease, which will allow us to design a study to validate these findings in a larger sample from an at-risk population of past plantation workers, and to test whether these patterns can be used as biomarkers for PD in this population and their offspring.
Final Outcome
DNA methylation is a mechanism that cells use to turn certain genes on and off. The aim of this study was to identify differences in DNA methylation in brain and blood samples between people with Parkinson's disease (PD) and healthy people. We evaluated differences in DNA methylation related to plantation work and/or exposure to organochlorine pesticides, both risk factors for PD. We aimed to determine how these DNA changes affect the risk of Parkinson's. The results of this study indicate that we can clearly differentiate between people with and without Parkinson's based on the changes in DNA methylation. Although this study included only a few participants, we were still able to recognize the difference between people with high and low levels of pesticide in their biosamples; the distinction was less clear for plantation work exposure.
We also found that two genes that influence the risk of PD, PARK2 and MAPT, were methylated differently in the high and low pesticide exposure groups, indicating that these two genes mediate the toxic effect of pesticides.
Our results indicate that DNA methylation plays an important role in Parkinson's disease and in the processes leading to the death of nerve cells after the exposure to pesticides. If confirmed in a larger study, sets of methylated genes found in blood cells should be investigated as possible biomarkers (objective measures) of Parkinson's. The methylation of these genes may indicate a major exposure to pesticides in the past.
October 2014