Study Rationale:
Several genetic and environmental factors determine the risk of developing Parkinson’s disease (PD) and how fast the disease progresses. We have identified 2 pesticides and air pollution associated with an increased risk of developing PD and with faster progression of the disease. Using a large, well-characterized human study population, stem cells generated from this population, and animal models, we will determine how these environmental toxicants alter risk and progression and the extent to which their actions are dependent on a person’s genetic background.
Hypothesis:
We hypothesize that environmental toxicants and genetic variation interact through specific molecular pathways to alter the risk of developing PD and the rate at which it progresses.
Study Design:
We will use advanced genetic and protein analyses to identify the molecular pathways impacted by these 3 toxicants in our human study population and determine why some people progress faster than others. We will culture brain cells made from stem cells derived from the blood of PD patients that have experienced varying toxicant exposures, and that show varying rates of disease progression, and expose these cells to the toxicants to determine how their DNA, RNA and proteins are altered. Using novel mouse and zebrafish models, in parallel with the human cells, we will identify the molecular pathways impacted by the 3 toxicants that determine the rate of disease progression. We will then make genetic changes in the human cells and in the animal models to prevent disease onset and/or slow progression.
Impact on Diagnosis/Treatment of Parkinson’s disease:
By determining the molecular mechanisms through which environmental toxicants increase PD risk and/or accelerate progression, and how this varies with genetic background, we can develop therapies to prevent high-risk individuals from developing PD and slow the progression of the disease in those that do contract PD.
Next Steps for Development:
With the results from these studies, measures to avoid exposures to these toxicants need to be implemented and treatments developed that will slow or stop progression of the disease.