Regulation of LRRK2 Expression Points to a Functional Role in Human Monocyte Maturation

Abstract

Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19⁺ B cells and in CD14⁺ monocytes, whereas CD4⁺ and CD8⁺ T cells were devoid of LRRK2 mRNA. Within CD14⁺ cells the CD14⁺CD16⁺ sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14⁺CD16^- cells. However both populations expressed LRRK2 mRNA. As CD14⁺CD16⁺ cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-γ in particular robustly increased LRRK2 mRNA and protein levels in monocytes concomitant with a shift of CD14⁺CD16⁻ cells towards CD14⁺CD16⁺cells. Interestingly, the recently described LRRK2 inhibitor IN-1 attenuated this shift towards CD14⁺CD16⁺ after IFN-γ stimulation. Based on these findings we speculate that LRRK2 might have a role in monocyte maturation. Our results provide further evidence for the emerging role of LRRK2 in immune cells and regulation at the transcriptional and translational level. Our data might also reflect an involvement of peripheral and brain immune cells in the disease course of PD, in line with increasing awareness of the role of the immune system in PD.