Study Rationale: Genome-wide association studies (GWAS) have unequivocally linked thousands of genetic variants to susceptibility for common, genetically complex Parkinson’s disease (PD), which affects more than 7 million people around the world. Why have these breakthroughs not uncovered the mechanism(s) of PD? We do not yet know how these disease-associated variants cause neurodegeneration or why they impair some brain cells but not others. Our research will tackle the critical task of clarifying the precise mechanisms through which this wealth of genetic variation regulates the onset and progression of PD.
Hypothesis: We hypothesize that most GWAS variants function by altering the regulation of genes in a cell-, space-, and stage-dependent manner.
Study Design: We will develop a molecular atlas that reveals how GWAS variants control disease mechanisms in five dimensions: brain cells (1D), brain space (3D) and disease stage (1D). We will reveal how genetic variants modulate specific brain cells in specific topographic locations during the progression of neuropathology from healthy brains to prodromal to symptomatic disease. To accomplish this, we will sequence the RNAs produced by hundreds of thousands of individual human brain cells, determine where in the brain variants arise and conduct cell- and stage-specific mechanistic analyses in Drosophila brains and in human pluripotent stem cells.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our project will translate PD genetics into a dynamic, five-dimensional view of cellular mechanisms. The results will begin to reveal how variations in single nucleotides alter gene activity in billions of specialized brain cells, and how these changes influence how, when and which brain cells are destined to malfunction.
Next Steps for Development: These results will provide high-priority targets — that are anchored in human genetics and mechanistically confirmed in stem cells and model animals — for drugs designed to prevent and slow common, sporadic PD.