Regulation of LRRK2 expression points to a functional role in human monocyte maturation.

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...

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Main Authors: Jonathan Thévenet, Rosanna Pescini Gobert, Robertus Hooft van Huijsduijnen, Christoph Wiessner, Yves Jean Sagot
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2011-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3124520?pdf=render
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spelling doaj-7775a445e7dd4b72ae9f6ca566f00ad62020-11-24T21:39:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2151910.1371/journal.pone.0021519Regulation of LRRK2 expression points to a functional role in human monocyte maturation.Jonathan ThévenetRosanna Pescini GobertRobertus Hooft van HuijsduijnenChristoph WiessnerYves Jean SagotGenetic 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.http://europepmc.org/articles/PMC3124520?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Jonathan Thévenet
Rosanna Pescini Gobert
Robertus Hooft van Huijsduijnen
Christoph Wiessner
Yves Jean Sagot
spellingShingle Jonathan Thévenet
Rosanna Pescini Gobert
Robertus Hooft van Huijsduijnen
Christoph Wiessner
Yves Jean Sagot
Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
PLoS ONE
author_facet Jonathan Thévenet
Rosanna Pescini Gobert
Robertus Hooft van Huijsduijnen
Christoph Wiessner
Yves Jean Sagot
author_sort Jonathan Thévenet
title Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
title_short Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
title_full Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
title_fullStr Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
title_full_unstemmed Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
title_sort regulation of lrrk2 expression points to a functional role in human monocyte maturation.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2011-01-01
description 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.
url http://europepmc.org/articles/PMC3124520?pdf=render
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