Leucine-rich repeat kinase 2 modulates cyclooxygenase 2 and the inflammatory response in idiopathic and genetic Parkinson's disease

Neurobiol Aging. 2014 May;35(5):1116-24. doi: 10.1016/j.neurobiolaging.2013.11.018. Epub 2013 Nov 22.


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.

Keywords: COX-2; Inflammation; LRRK2; NFκB; Parkinson's disease; RNA-binding proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Fibroblasts / enzymology
  • Humans
  • Inflammation / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Middle Aged
  • Molecular Targeted Therapy
  • Mutation*
  • NF-kappa B / genetics
  • Parkinson Disease / drug therapy
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / physiology*
  • RNA / metabolism
  • Transcriptional Activation


  • NF-kappa B
  • RNA
  • Cyclooxygenase 2
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases