Dissecting the genetic interactions controlling α-Synuclein accumulation in Parkinson’s Disease

Genetic risk constitutes complex interactions among numerous genomic loci to affect disease susceptibility. Given the simultaneous involvement of numerous genetic factors, and the difficulty to identify the relevant affected genes by genome-wide association studies (GWAS), it has been notoriously difficult to define the most critical pathways for further functional testing. In this proposal I will use a novel technology to define, in a high throughput and unbiased manner, which GWAS-associated genes cause risk in Parkinson’s disease (PD) and how their functional and complex genetic interactions are shaped. The most recent GWAS of PD identified 90 risk variants across 78 genomic loci. I will use a novel dual CRISPR inhibition/activation tool that I recently developed to up- and downregulate combinations of genes associated with these GWAS signals in human dopaminergic neurons, the preferentially affected cell type in PD. I will then use a combination of CROPseq and CITEseq to correlate these gene combinations in a high throughput manner to the levels of α-Synuclein, that is a major hallmark of PD. I will focus on gene combinations that lower α-Synuclein abundance as those are expected to be protective, and conduct molecular work that my host lab is proficient in to define the causative pathways. This project takes a conceptual new approach and brings functional insight into GWAS and complex human genetic interactions in a major neurodegenerative disease.