Environmental Modulation of Alpha-Synuclein Neurotoxicity in Parkinson s Disease
Abstract
Our research falls within the Department of Defense Parkinson s Research Program’s stated focus area of studying gene-environment (GxE) interactions in Parkinson s disease cohorts. Although there are many genes and many environmental exposures that are known to influence the risk of developing Parkinson s disease, there are likely many more that are as yet undiscovered, and the ways in which genes and environment combine to influence risk together is not understood. The objective of this project is to identify novel gene-environment interactions and, for known interactions, to understand how they influence the risk of developing Parkinson s disease. In the first aim, we will identify new GxE interactions using genetic and environmental data collected on patients with Parkinson s disease through the Harvard Biomarkers Study and Parkinson s Progression Marker Initiative programs. We will then validate any findings in an additional cohort of patients to ensure they are generalizable. In the second aim, we will investigate two genes that are already known to influence risk through interaction with environmental factors: the gene GRIN2A with coffee and the gene SV2C with smoking. We will manipulate levels of expression of these genes with and without simultaneous exposure to caffeine and nicotine using a Drosophila (fruit fly) model of Parkinson s disease, in which the flies develop parkinsonism because of overexpression of human alpha-synuclein. This will allow us to determine whether it is the amount of the gene expressed that influences the risk of developing Parkinson s disease and whether the influence occurs through pathways involving alpha-synuclein. Eventually, this type of research will allow us to understand why some people develop Parkinson s disease and why the underlying reason may be different from one patient to another. This is very important to ultimately understanding how we might be able to prevent Parkinson s disease in people who are at risk. In the more immediate future, this research may help patients who already have Parkinson s disease in multiple ways. First, it may have a dramatic impact on clinical trial design. For example, if we find that a certain subpopulation of patients carries a gene that interacts with coffee consumption to modify risk of disease, then it would be logical to put those patients in a clinical trial of caffeine as a therapy for Parkinson s disease. Second, by understanding how genes and environment work together to influence risk, we can determine what specifically causes the risk and therefore find new targets for new therapeutics. The ultimate goal behind this research is to realize a future of personalized medicine, in which individual patients get specific therapies based on their individual genetics. We expect this to happen over the coming years. I am currently a Movement Disorders Fellow, and my goal after this training period is to have my own laboratory specializing in Parkinson s disease research. Specifically, I would like to combine work with human samples and model organisms (like Drosophila) to better understand Parkinson s disease and ultimately generate new therapies for it. The research and mentorship plan proposed here has been carefully crafted to allow me to realize this goal. While completing the scientific aims, I will in parallel be completing specific training objectives. I will take courses and gain concrete new skills, including developing a familiarity with specific programs in statistics, computer programming, and bioinformatics, which is now required to work with big datasets for human genetic studies. I will also gain a deeper understanding of the power of Drosophila as a model organism and learn specific techniques for studying Drosophila neurobiology. I will be presenting my research at local and national meetings. My mentors, Dr. Mel Feany and Dr. Clemens Scherzer, are experts in the fields of Drosophila neurodegeneration and human genomics in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810395
Entities
People
- Abby Olsen
Organizations
- United States Army