caa a22 4500 445377429 CHVBK 20180317143007.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00702-011-0653-2 doi (NATIONALLICENCE)springer-10.1007/s00702-011-0653-2 Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures [Elektronische Daten] [Mansoureh Hakimi, Thirumahal Selvanantham, Erika Swinton, Ruth Padmore, Youren Tong, Ghassan Kabbach, Katerina Venderova, Stephen Girardin, Dennis Bulman, Clemens Scherzer, Matthew LaVoie, Denis Gris, David Park, Jonathan Angel, Jie Shen, Dana Philpott, Michael Schlossmacher] 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 (>260kDa) 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. Springer-Verlag, 2011 Parkinsonism nationallicence Terminal ileitis nationallicence Hansen's disease nationallicence Lymphocyte nationallicence Monocyte nationallicence Macrophage nationallicence Leucine-rich repeat protein nationallicence Pattern recognition molecule nationallicence Toll-like receptor nationallicence Autophagy nationallicence LC3 nationallicence Kinase nationallicence Cytokine nationallicence Interleukin nationallicence Hakimi Mansoureh Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut Selvanantham Thirumahal Department of Immunology, University of Toronto, Toronto, ON, Canada aut Swinton Erika Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut Padmore Ruth Department of Ophthalmology, University of Ottawa Eye Institute and The Ottawa Hospital, Ottawa, ON, Canada aut Tong Youren Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut Kabbach Ghassan Program in Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada aut Venderova Katerina Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut Girardin Stephen Department of Immunology, University of Toronto, Toronto, ON, Canada aut Bulman Dennis Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada aut Scherzer Clemens Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut LaVoie Matthew Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut Gris Denis Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA aut Park David Program in Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada aut Angel Jonathan Division of Infectious Diseases, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada aut Shen Jie Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut Philpott Dana Department of Immunology, University of Toronto, Toronto, ON, Canada aut Schlossmacher Michael Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut Journal of Neural Transmission Springer Vienna 118/5(2011-05-01), 795-808 0300-9564 118:5<795 2011 118 702 https://doi.org/10.1007/s00702-011-0653-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-011-0653-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hakimi Mansoureh Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Selvanantham Thirumahal Department of Immunology, University of Toronto, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Swinton Erika Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Padmore Ruth Department of Ophthalmology, University of Ottawa Eye Institute and The Ottawa Hospital, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Tong Youren Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Kabbach Ghassan Program in Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Venderova Katerina Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Girardin Stephen Department of Immunology, University of Toronto, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Bulman Dennis Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Scherzer Clemens Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- LaVoie Matthew Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Gris Denis Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA aut NATIONALLICENCE 700 1- Park David Program in Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Angel Jonathan Division of Infectious Diseases, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada aut NATIONALLICENCE 700 1- Shen Jie Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Philpott Dana Department of Immunology, University of Toronto, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Schlossmacher Michael Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, K1H 8M5, Ottawa, ON, Canada aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/5(2011-05-01), 795-808 0300-9564 118:5<795 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer