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

  • Movement Disorders - Original Article
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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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Acknowledgment

This manuscript was contributed in honor of Dr. Kurt A. Jellinger’s 80th birthday and his distinguished career. We thank the editor for its solicitation. This work was supported by grants from the Government of Canada [Canada Research Chair Program (to M.G.S.)], the Michael J. Fox Foundation for Parkinson’s Research [LRRK2 Award; Supplementary LRRK2 Award (to D.S.P., J.S., M.G.S.)], the Parkinson Research Consortium Ottawa (to D.S.P., M.G.S.) and the National Institutes of Health (NIH grant R01NS064155 to C.R.S.). We are grateful for critical comments by Drs. D. Galter, W. Schulz-Schaeffer, S. Hayley, and J. Ngsee and for the assistance of Dr. I. Irrcher, Dr. J. Woulfe, A. Given and E. Abdel-Messih. Dr. K. Venderova is now at the University of the Pacific, Stockton, CA, USA.

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  1. Division of Neuroscience, Ottawa Hospital Research Institute, 451 Smyth Road, Roger Guindon Hall, Ottawa, ON, K1H 8M5, Canada

    Mansoureh Hakimi, Erika Swinton, Katerina Venderova & Michael G. Schlossmacher

  2. Program in Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

    Mansoureh Hakimi, Ghassan Kabbach, David S. Park & Michael G. Schlossmacher

  3. Department of Immunology, University of Toronto, Toronto, ON, Canada

    Thirumahal Selvanantham, Stephen E. Girardin & Dana J. Philpott

  4. Department of Ophthalmology, University of Ottawa Eye Institute and The Ottawa Hospital, Ottawa, ON, Canada

    Ruth F. Padmore

  5. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Youren Tong, Clemens R. Scherzer, Matthew J. LaVoie & Jie Shen

  6. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Dennis E. Bulman

  7. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA

    Denis Gris

  8. Division of Infectious Diseases, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

    Jonathan B. Angel

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  1. Mansoureh Hakimi
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Supplementary material 1 (PDF 234 kb) Supplementary Figure 1: LRRK2 mRNA and protein detection in EBV-transformed lymphoblasts and peripheral blood mononuclear cells. (A–D) Reducing SDS/PAGE was carried out using lysates of Ficoll-separated peripheral blood mononuclear cells (PBMC) from one human control donor (lane 3), followed by Western blotting with four different monoclonal rabbit anti-Lrrk2 antibodies (provided by the Michael J Fox Foundation, MJFF; see Materials and Methods), as indicated. Transgenic flies expressing full-length human LRRK2 cDNA (tg; lane 1) and their control littermates (wt; lane 2) were used as positive and negative controls, respectively. Note, the specific detection of full-length Lrrk2 (260 kDa), and higher molecular weight (HMW) species thereof in PBMC lysates, as well as of HMW Lrrk2 reactivity in tg fly homogenates. Membranes were stripped and redeveloped with anti-β-actin antibody (lower panels). (E) LRRK2, GAPDH transcripts and 18S RNA isolated from EBV-transformed lymphoblasts from a healthy donor were processed by reverse transcriptase and PCR to generate distinct amplification products, as indicated (for primer pairs, see Materials and Methods).

702_2011_653_MOESM2_ESM.pdf

Supplementary material 2 (PDF 156 kb) Supplementary Figure 2: Murine Lrrk2 expression in cells from immune organs and exploration of its role in cytokine release by genotyped macrophages. (A) FACS-based quantification of lrrk2-positive immune cells isolated from homogenates of spleen and mesenteric lymph nodes of wild-type mice (n = 3) as described (Werts et al. 2007). Note, among four distinct leukocyte populations sorted, neutrophils revealed the strongest signal for lrrk2 reactivity (see also Discussion). Lrrk2 expression was measured by FACS analysis using anti-Lrrk2 antibody MJFF-4 on B220+ B-cells, TCRβ+ T-cells, CD11b+/CD11c+ macrophages, Gr-1+ neutrophils, and CD11c+ dendritic cells. (B) Lrrk2-genotype dependent cytokine signaling following exposure to different stimulants was explored by probing IL-6 and KC release by ELISA (Werts et al. 2007) from cultured BMDM. Cells were isolated from R1441C lrrk2 knock-in (KI) mice, heterozygous (HET) animals, and age-matched wild-type (WT) littermates (12 weeks old, n = 2 each; supernatants were analyzed in quadruplicates). Note, no consistent lrrk2 genotype-associated effect (WT vs. HET / KI) was detected in the conditioned media of BMDM cells.

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Hakimi, M., Selvanantham, T., Swinton, E. et al. Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm 118, 795–808 (2011). https://doi.org/10.1007/s00702-011-0653-2

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