Influence of genotype on microglia phenotype and function in PD

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 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) characterized by the accumulation and aggregation of a-synuclein in which the dopaminergic neurons of the substantia nigra die. The innate immune system is thought to play a role in the demise of these neurons. Therefore, we hypothesized that genotypic differences in microglia are involved in the pathophysiology of PD and, particularly, in the death of these dopamine producing cells. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 11 PD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in the innate immune cell type monocytes and not in T cells that represent the adaptive arm of the immune system. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to PD pathology. The principal goals of the proposed project are (1) to identify the component genes of networks perturbed by the PD susceptibility loci in myeloid cells (2) to understand their functional consequences on microglia behavior and (3) examine the role of these susceptibility loci on CNS microglia activation and gene expression.