title: Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells.
abstract: BACKGROUND
  Over-activated microglia and chronic neuroinflammation contribute to dopaminergic neuron degeneration and progression of Parkinson's disease (PD). Leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in autosomal dominantly inherited and sporadic PD cases, is highly expressed in immune cells, in which it regulates inflammation through a yet unclear mechanism.
  
  
  METHODS
  Here, using pharmacological inhibition and cultured Lrrk2 (-/-) primary microglia cells, we validated LRRK2 as a positive modulator of inflammation and we investigated its specific function in microglia cells.
  
  
  RESULTS
  Inhibition or genetic deletion of LRRK2 causes reduction of interleukin-1β and cyclooxygenase-2 expression upon lipopolysaccharide-mediated inflammation. LRRK2 also takes part of the signaling trigged by α-synuclein fibrils, which culminates in induction of inflammatory mediators. At the molecular level, loss of LRRK2 or inhibition of its kinase activity results in increased phosphorylation of nuclear factor kappa-B (NF-κB) inhibitory subunit p50 at S337, a protein kinase A (PKA)-specific phosphorylation site, with consequent accumulation of p50 in the nucleus.
  
  
  CONCLUSIONS
  Taken together, these findings point to a role of LRRK2 in microglia activation and sustainment of neuroinflammation and in controlling of NF-κB p50 inhibitory signaling. Understanding the molecular pathways coordinated by LRRK2 in activated microglia cells after pathological stimuli such us fibrillar α-synuclein holds the potential to provide novel targets for PD therapeutics.
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Russo
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Berti
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.|Current address: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Plotegher
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Greta
authors.initials: G
authors.lastname: Bernardo
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.|Current address: Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Roberta
authors.initials: R
authors.lastname: Filograna
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.affiliation: Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy. elisa.greggio@unipd.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D052002:NF-kappa B p50 Subunit; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases