Study Rationale: Although thousands of DNA variants are linked to Parkinson’s disease (PD), their exact functions are unknown. These variants are in the “dark matter” of our genome and do not lead to the production of mutant proteins. The goal of our study is to determine how these DNA variants cause glitches in the RNA “software” of brain cells and to use these variants to simulate the genetic program of PD brain cells on a computer.
Hypothesis: We hypothesize that most PD-associated DNA variants function by altering the regulation of gene activity in a cell-, space-, and stage-dependent manner.
Study Design: Using our “5D” molecular atlas of PD — which records cell type (1D), 3D location in the brain and disease progression (1D) — we will sequence the RNA of millions of human brain cells and spatially map hundreds of brain samples to reveal PD genes. In what may be one of the largest studies of human brain cells to date, we will systematically examine several mechanisms through which DNA variants can disrupt RNA programs in up to sixteen different types of brain cells. The PD genes identified will be tested in stem cells using CRISPR gene editing and in fruit fly PD models.
Impact on Diagnosis/Treatment of Parkinson’s disease: This study will begin to reveal how variation in a person’s DNA alters gene regulation in millions of physiologically specialized neurons and glia cells. Determining how, when, where and which brain cells are destined to malfunction will bridge the promise of genome-wide screens to identify PD genes and therapeutic targets.
Next Steps for Development: These results will provide high-priority targets — anchored in human genetics and mechanistically confirmed in stem cells and preclinical models — for drugs designed to prevent and slow common, sporadic PD.