A LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblasts

Cells. 2021 Feb 23;10(2):480. doi: 10.3390/cells10020480.


Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn's disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.

Keywords: GTP binding inhibitor; LPS; LRRK2; Parkinson’s disease; TNF-α; lymphoblast.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Enzyme Activation / drug effects
  • Guanosine Triphosphate / metabolism*
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Models, Biological
  • NF-KappaB Inhibitor alpha / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*


  • Lipopolysaccharides
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Guanosine Triphosphate
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2