The role of LRRK2 in the regulation of monocyte adhesion to endothelial cells

J Mol Neurosci. 2015 Jan;55(1):233-239. doi: 10.1007/s12031-014-0312-9. Epub 2014 May 1.

Abstract

The leucine-rich repeat kinase 2 (LRRK2) gene was discovered to encode a member of an evolutionarily conserved family of proteins marked by GTPase domains usually in combination with kinase domains. Missense mutations in both the kinase and GTPase domains in LRRK2 have been found to cause late-onset Parkinson's disease (PD). In this study, we investigated the effects of the LRRK2 on endothelial inflammation. We first demonstrated that the LRRK2 is expressed in endothelial cells. We also report here that IL-1β can possibly increase LRRK2 expression in human umbilical vein endothelial cells (HUVECs). Wild-type LRRK2 (LRRK2(wt)) expression induces expression of vascular cell adhesion molecule 1 (VCAM-1) which is further exacerbated in cells expressing PD-associated LRRK2 G2019S mutants (LRRK2(G2019S)). Importantly, induction of VCAM-1 is almost completely blocked in cells expressing the GTP-binding-deficient mutant K1347A of LRRK2 (LRRK2(K1347A)). In addition, overexpression of LRRK2(wt) and LRRK2(G2019S) were found to cause an increase in monocyte attachment to endothelial cells. Mechanistically, we found that LRRK2 increases the transcriptional activity of nuclear factor κB (NF-κB) by increasing phosphorylation levels of IκBα. These findings suggest that inhibition of LRRK2 kinase activity may be a potential target for treatment of endothelial dysfunction.

MeSH terms

  • Cell Adhesion
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Inflammation / metabolism
  • Interleukin-1beta / pharmacology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Monocytes / metabolism*
  • Monocytes / physiology
  • Mutation
  • NF-kappa B / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Interleukin-1beta
  • NF-kappa B
  • Vascular Cell Adhesion Molecule-1
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases