Abstract
The Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson’s disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn’s disease (CD). LRRK2 is expressed in human CD14+ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14+ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14+ cells in CD but not in control group. CD14+ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response.Graphical
Highlights
The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a causative gene of familial Parkinson’s disease (PD) (Cookson 2010)
Since LRRK2 is highly expressed in myeloid cells, we used CD14+ monocytes isolated from peripheral blood mononuclear cells (PBMCs) using magnetic bead cell isolation
Ex vivo stimulation of CD14+ monocytes with IFN-γ induced gene expression of inflammatory cytokines (TNFA and IL12), major histocompatibility complex molecules (HLADRA1), and LRRK2, which was signifcantly suppressed by FK506 (Fig. 2), a specific inhibitor of calcineurin and known inhibitor of Nuclear Factor of Activated T cells (NFAT) pathway via enhancing its phosphorylationdependent degradation (Liu et al 2011)
Summary
The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a causative gene of familial PD (Cookson 2010). In situ hybridization and Northern blotting results revealed surprisingly low signals for LRRK2 mRNA in brain, especially very low levels in critical PD sites including the SN (Zimprich et al 2004; Galter et al 2006)
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