(SUPPLEMENT) Using Single-cell Analyses to Understand Inherited and Acquired Genetic Variation in Parkinson’s Disease

Study Rationale: Parkinson’s disease (PD) is a disorder that not only affects the function of the brain, but also the gut. Both of these are complex tissues composed of functionally diverse cell types that must cooperate for proper organ function. Approximate 90 regions of the DNA that we inherit from our parents show differences between people with and without PD. Furthermore, as we age, new, non-inherited DNA mutations can also arise in our cells. How such inherited and newly acquired DNA variants function in increasing the risk of developing PD remains largely unknown.

Hypothesis: We hypothesize that DNA variants, both inherited and acquired, can alter the activity of key genes in cells of the brain and the gut, increasing the risk of developing PD.

Study Design: We will leverage our expertise in analyzing individual cells to study post mortem samples of the brain and gut from people with and without PD. Specifically, cataloging gene expression in more than 4,500,000 single cells will allow us to discover the genes for which the expression is altered by DNA variants and the specific cell types in which the expression of each gene is disturbed. We will next analyze how these DNA variants change the functioning of these specific cell types, using our existing fruit fly models and cultured human nerve and immune gut cells.

Impact on Diagnosis/Treatment of Parkinson’s disease: This study will provide crucial mechanistic insights into how differences in our DNA change the functioning of specific cells in our brains and guts, enhancing the predisposition to developing PD.

Next Steps for Development: The insights developed here can allow for the identification of novel biomarkers as well as for the rational design of novel treatments to slow PD progression by targeting the differences we uncover in specific cells of the brain and gut.