Parkinson’s disease (PD) is a progressive, neurodegenerative disorder of aging that affects both motor and cognitive function. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Genome-­wide association studies (GWAS) have identified many regions harboring variants associated with PD. The next challenge in translational research is to identify the causal variants underlying the association signals, the affected genes, molecular pathways and their functional consequences. Because genetic variants can mediate effects on higher-­order phenotypes through effects on gene expression, the integration of transcriptomics into the study of disease associated variants has already proven to be a useful strategy, and indeed disease associated loci have been shown to be enriched for variants regulating gene expression. We have recently shown that genetic variants that affect gene expression in myeloid cells underlie a substantial fraction of the genetic associations to PD. We have also accumulated compelling data suggesting that many genes involved in autophagy-­lysosomal pathways and mitochondrial function are differentially expressed in monocytes and in microglia of PD cases compared to controls and in some cases, are genetically regulated by PD-­associated genetic variants. Here, in aim 1, we will generate bulk and single cell transcriptome and proteome profiles from 250 peripheral monocytes of early-­stage PD (with no medication, within 2 years from the onset of the symptoms), mid-­ to late-­stage PD, and age-­matched controls from a well-­characterized PD cohort. The sample collection and transcriptome profiles will be done longitudinally (at baseline and follow up within 2 years). In aim 2, will characterize the transcriptome of primary microglia from multiple regions of autopsied brains of PD cases and age-­matched controls and explore the consequences on the transcriptome of PD susceptibility variants. We will conduct state-­of-­the-­art analyses that will integrate multi-­omic and clinical data sets to generate patient derived, data-­driven, multi-­scale models of disease, enabling the generation of hypotheses around protein interactions specific to disease states and subgroups. In aim 3, we will functionally characterize monocytes and microglia in order to investigate the effects that gene expression, protein abundance and network connectivity changes may have on immune functions of interest such as: 1) phagocytic capacity;; 2) lysosomal function;; and 3) mitochondrial activity. This project will have a large overall impact by: 1) providing key information bridging PD genetics to molecular mechanisms in monocytes and microglia, setting the stage for future mechanistic studies;; and (2) generating large-­scale, multi-­omic datasets, together with systems level analyses of these datasets in innate immune cells, which is an urgently needed resource.

The long-term goal of this project is to deepen our understanding of the role of peripheral monocytes and microglia in Parkinson’s Disease (PD) and to identify myeloid-related targets for treatment of the disease. If successful, discoveries from this study will provide a foundation for more ambitious plans to identify potential mechanisms and modulating factors for the increased risk of PD. Our proposed work may explain the causes of PD and have the potential to lead to new therapeutic targets for PD.