Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway

Cell Signal. 2010 May;22(5):821-7. doi: 10.1016/j.cellsig.2010.01.006. Epub 2010 Jan 13.


Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of autosomal-dominant Parkinson's disease (PD). The second known autosomal-dominant PD gene (SNCA) encodes alpha-synuclein, which is deposited in Lewy bodies, the neuropathological hallmark of PD. LRRK2 contains a kinase domain with homology to mitogen-activated protein kinase kinase kinases (MAPKKKs) and its activity has been suggested to be a key factor in LRRK2-associated PD. Here we investigated the role of LRRK2 in signal transduction pathways to identify putative PD-relevant downstream targets. Over-expression of wild-type [wt]LRRK2 in human embryonic kidney HEK293 cells selectively activated the extracellular signal-regulated kinase (ERK) module. PD-associated mutants G2019S and R1441C, but not kinase-dead LRRK2, induced ERK phosphorylation to the same extent as [wt]LRRK2, indicating that this effect is kinase-dependent. However, ERK activation by mutant R1441C and G2019S was significantly slower than that for [wt]LRRK2, despite similar levels of expression. Furthermore, induction of the ERK module by LRRK2 was associated to a small but significant induction of SNCA, which was suppressed by treatment with the selective MAPK/ERK kinase inhibitor U0126. This pathway linking the two dominant PD genes LRRK2 and SNCA may offer an interesting target for drug therapy in both familial and sporadic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Butadienes / pharmacology
  • Cell Line
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • MAP Kinase Kinase 2 / metabolism
  • MAP Kinase Signaling System* / drug effects
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Nitriles / pharmacology
  • Parkinson Disease / enzymology
  • Parkinson Disease / pathology
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Time Factors
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism


  • Butadienes
  • Mutant Proteins
  • Nitriles
  • RNA, Messenger
  • U 0126
  • alpha-Synuclein
  • MAP2K2 protein, human
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 2