Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells

Sci Rep. 2017 Aug 31;7(1):10300. doi: 10.1038/s41598-017-10501-z.


Genetic variation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with risk of familial and sporadic Parkinson's disease (PD). To support clinical development of LRRK2 inhibitors as disease-modifying treatment in PD biomarkers for kinase activity, target engagement and kinase inhibition are prerequisite tools. In a combined proteomics and phosphoproteomics study on human peripheral mononuclear blood cells (PBMCs) treated with the LRRK2 inhibitor Lu AF58786 a number of putative biomarkers were identified. Among the phospho-site hits were known LRRK2 sites as well as two phospho-sites on human Rab10 and Rab12. LRRK2 dependent phosphorylation of human Rab10 and human Rab12 at positions Thr73 and Ser106, respectively, was confirmed in HEK293 and, more importantly, Rab10-pThr73 inhibition was validated in immune stimulated human PBMCs using two distinct LRRK2 inhibitors. In addition, in non-stimulated human PBMCs acute inhibition of LRRK2 with two distinct LRRK2 inhibitor compounds reduced Rab10-Thr73 phosphorylation in a concentration-dependent manner with apparent IC50's equivalent to IC50's on LRRK2-pSer935. The identification of Rab10 phosphorylated at Thr73 as a LRRK2 inhibition marker in human PBMCs strongly support inclusion of assays quantifying Rab10-pThr73 levels in upcoming clinical trials evaluating LRRK2 kinase inhibition as a disease-modifying treatment principle in PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology / methods
  • Dose-Response Relationship, Drug
  • Humans
  • Immunomodulation / drug effects
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proteome
  • Proteomics
  • Reproducibility of Results
  • rab GTP-Binding Proteins / metabolism*


  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Proteome
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Rab10 protein, human
  • Rab12 protein, human
  • rab GTP-Binding Proteins