Parkinson5D: Deconstructing Proximal Disease Mechanisms across Cells, Space and Progression

Study Rationale:
Genome-wide association studies (GWAS) have unequivocally linked thousands of noncoding variants in 90 independent GWAS signals to susceptibility for common, genetically complex Parkinson’s disease (PD) that affects more than 6 million people around the world. Why have these breakthroughs not uncovered the mechanism(s) of PD? We do not know how disease-associated variants cause neurodegeneration and 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 onset and progression of PD.

Hypothesis:
We hypothesize that most GWAS variants function through cell-, space-, and stage-dependent gene-regulatory mechanisms.

Study Design:
Here we will develop a molecular atlas of PD that reveals how GWAS/familial genetics control proximal disease mechanisms in five dimensions: brain cells (1D), brain space (3D) and disease stage (1D). We will reveal how genetic variants modulate mechanisms in specific brain cells in specific topographic locations of midbrain and cortex during the progression of neuropathology from healthy brains to prodromal to symptomatic disease. Massively parallel analysis of hundreds of thousands of single human brain cells with genetic transcriptomics, high-resolution spatial transcriptomics, and fine-mapping of causal alleles with allelic imbalance in human brains will be combined with the prodigious power of cell- and stage-specific mechanistic analyses in brain of Drosophila avatars and in vitro in human pluripotent stem cells.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our collaborative and integrative project will translate the complex human genetics of PD into a dynamic, five-dimensional view of proximal cellular mechanisms. It will begin to reveal how single nucleotide variation in a person’s universal DNA code regulates gene activity (without changing protein sequence) in situ in billions of physiologically specialized neurons and glia cells, and determines, how, when, which, and where brain cells are destined to malfunction.