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

Jonathan Thévenet,Robertus Hooft Van Huijsduijnen,Christoph Wiessner,Rosanna Pescini Gobert,Yves Jean Sagot,Silvano Sozzani

doi:10.1371/journal.pone.0021519

Jonathan Thévenet, Robertus Hooft Van Huijsduijnen + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0021519

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Journal: PloS one	Publication Date: Jun 27, 2011
Citations: 205	License type: CC BY 4.0

Affiliation: Merck Serono (Switzerland)

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.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1.5% of the population over 50 years [1]
Leucine-Rich Repeat Kinase 2 (LRRK2) expression in hPBMC and hPBMC sub-populations Recent publications and expression database analyses highlight the fact that LRRK2 mRNA is abundantly expressed in spleen and B lymphocytes [12,14]
In this study we further evaluated LRRK2 expression in peripheral blood mononuclear cells (PBMCs) at the mRNA and protein levels

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1.5% of the population over 50 years [1]. Since LRRK2 deficient [8] or LRRK2 wt over-expressing [9] transgenic mice do not present severe clinical neurological symptoms it seems likely that pathological mutations are not associated with a simple gain or loss of kinase or GTPase activity (for review [10]). These studies rely on artificially over-expressing or knocking down LRRK2 expression. Experiments using LRRK2 kinase inhibitors suggest that LRRK2 may play an important role in monocyte responses to IFN-c. From a clinical perspective our data suggest that hPBMC and monocytes derived from hPBMCs might yield biomarkers for therapeutic LRRK2 inhibitors

Materials and Methods

Results

Discussion