Dysregulation of mitochondrial and proteolysosomal genes in Parkinson’s disease myeloid cells

Abstract

An increasing number of identified Parkinson’s disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesized that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we generated transcriptomic profiles of monocytes from healthy subjects and 230 individuals with sporadic PD. We observed dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, was altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.