title: Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) have been causally linked to neuronal cell death in Parkinson's disease. LRRK2 expression has also been detected in B lymphocytes and macrophages, suggesting a role in immune responses. In the present study, we demonstrate that LRRK2 is expressed in primary microglial cells isolated from brains of adult mice. Moreover, lipopolysaccharide (LPS)-activated microglial cells from mice overexpressing the Parkinson's disease-linked LRRK2(R1441G) mutation exhibit increased expression and secretion of proinflammatory cytokines compared with wild-type control microglia. Expression of the LPS receptor Toll-like receptor 4 (TLR4) and downstream signaling proteins did not differ between LRRK2(R1441G) transgenic microglia and wild-type controls. Consistently, conditioned medium from LPS-stimulated LRRK2(R1441G) transgenic microglia induced significant cell death when added to neuronal cultures. These findings indicate that enhanced neuroinflammation may contribute to neurodegeneration in Parkinson's disease patients carrying LRRK2 mutations.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, CNS Research, Birkendorfer Strasse 65, 88397 Biberach, Germany. Frank.Gillardon@boehringer-ingelheim.com
authors.forename: F
authors.initials: F
authors.lastname: Gillardon
authors.forename: R
authors.initials: R
authors.lastname: Schmid
authors.forename: H
authors.initials: H
authors.lastname: Draheim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases