Study Rationale: Both environmental and genetic factors are believed to be involved in Parkinson’s disease (PD). Although the genetic mutations linked to PD have been studied intensively, it is estimated that heritability only accounts for about 30% of PD causality. Multiple environmental toxins, including pesticides, have been associated with PD. But studies of their underlying mechanisms have lagged the breakthroughs in genetics. In this project, we will establish a standardized platform to study the effects of environmental factors on human brain cells. We will use established assays to detect cellular phenotypes related to PD pathology.
Hypothesis: We hypothesize that our platform will allow us to identify environmental toxins related to PD development, help us to understand their underlying disease mechanisms and facilitate the development of new policies to regulate use of these compounds.
Study Design: We will use stem cell lines to produce human brain cells, including dopamine neurons and oligodendrocytes. We will use these cells to screen a panel of environmental compounds for their ability to induce cell death. Using established PD-relevant cellular assays, we will also screen compounds for their ability to induce specific PD phenotypes. Lastly, we will develop chemical probes against a selection of the most toxic compounds and identify their cellular targets.
Impact on Diagnosis/Treatment of Parkinson’s disease: The ability to screen for toxins that induce PD-relevant phenotypes will allow us to investigate how environmental exposures contribute to the pathology of PD, examine how environmental factors interact with genetic factors associated with PD and facilitate the development of safer alternatives to toxic compounds and the reform of related policies.
Next Steps for Development: After establishing this platform using healthy cell lines and an initial panel of compounds, we will examine the toxicity of a wider range of chemicals and test relevant toxins on stem-cell lines with known PD-associated gene modifications to understand the interplay between environmental factors and genetics in PD.