title: Leucine-rich repeat kinase 2 modulates cyclooxygenase 2 and the inflammatory response in idiopathic and genetic Parkinson's disease.
abstract: Inflammatory mechanisms are activated in aging and late-onset neurodegenerative diseases, such as Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both idiopathic and familial forms of PD. Here, we investigated the involvement of LRRK2 in inflammatory pathways using primary dermal fibroblasts from patients with 2 common mutations in LRRK2 (G2019S and R1441G), idiopathic PD and age-matched healthy individuals. Basal cyclooxygenase (COX)-2 RNA levels were very high in the fibroblasts of all patients. Remarkably, LRRK2 silencing experiments significantly reduced basal COX-2 levels and COX-2 induction after a pro-inflammatory stimulus. Additionally, in samples from patients with the R1441G mutation and with idiopathic PD, we found a prominent cytoplasmic re-distribution of human antigen R, a protein that, among others, stabilizes COX-2 RNA. Furthermore, the response to lipopolysaccharide was defective in these 2 groups, which showed weak induction of pro-inflammatory cytokines and reduced NFκB transcriptional activation. In summary, we describe multiple defects in inflammatory pathways in which LRRK2 appears to be critically involved. Further studies are required to establish the therapeutic implications of inflammatory dysregulation in the pathophysiology of Parkinson's disease.
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Rakel
authors.initials: R
authors.lastname: Lopez de Maturana
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Aguila
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Amaya
authors.initials: A
authors.lastname: Sousa
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Vazquez
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Del Rio
authors.affiliation: Neuroscience Area, Biodonostia Institute, San Sebastián, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aiastui
authors.affiliation: Neuroscience Area, Biodonostia Institute, San Sebastián, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.affiliation: Neuroscience Area, Biodonostia Institute, San Sebastián, Spain; Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain; Deparment of Neurosciences, University of the Basque Country, San Sebastián, Spain; CIBERNED (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas), Carlos III Institute, Ministry of Economy and Competitiveness, San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain
authors.affiliation: Laboratory of Stem Cells and Neural Repair, Fundación Inbiomed, San Sebastián, Spain. Electronic address: rpernaute@inbiomed.org.
authors.forename: Rosario
authors.initials: R
authors.lastname: Sanchez-Pernaute
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D016328:NF-kappa B; D012313:RNA; D051546:Cyclooxygenase 2; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: COX-2; Inflammation; LRRK2; NFκB; Parkinson's disease; RNA-binding proteins