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01-05-2011 | Movement Disorders - Original Article

Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures

Authors: Mansoureh Hakimi, Thirumahal Selvanantham, Erika Swinton, Ruth F. Padmore, Youren Tong, Ghassan Kabbach, Katerina Venderova, Stephen E. Girardin, Dennis E. Bulman, Clemens R. Scherzer, Matthew J. LaVoie, Denis Gris, David S. Park, Jonathan B. Angel, Jie Shen, Dana J. Philpott, Michael G. Schlossmacher

Published in: Journal of Neural Transmission | Issue 5/2011

Abstract

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn’s disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14⁺ monocytes, CD19⁺ B cells, and CD4⁺ as well as CD8⁺ T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14⁺ monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in ^R1441Clrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor-type function for LRRK2 could explain its locus' association with Crohn’s disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression.

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Title: Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures
Authors: Mansoureh Hakimi
Thirumahal Selvanantham
Erika Swinton
Ruth F. Padmore
Youren Tong
Ghassan Kabbach
Katerina Venderova
Stephen E. Girardin
Dennis E. Bulman
Clemens R. Scherzer
Matthew J. LaVoie
Denis Gris
David S. Park
Jonathan B. Angel
Jie Shen
Dana J. Philpott
Michael G. Schlossmacher
Publication date: 01-05-2011
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 5/2011
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-011-0653-2

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Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures

Abstract

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Abstract

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