Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity

PLoS One. 2016 Mar 1;11(3):e0149739. doi: 10.1371/journal.pone.0149739. eCollection 2016.

Abstract

Background: Recent studies have linked certain single nucleotide polymorphisms in the leucine-rich repeat kinase 2 (LRRK2) gene with Parkinson's disease (PD). Among the mutations, LRRK2 c.4883G>C (R1628P) variant was identified to have a significant association with the risk of PD in ethnic Han-Chinese populations. But the molecular pathological mechanisms of R1628P mutation in PD is still unknown.

Principle findings: Unlike other LRRK2 mutants in the Roc-COR-Kinase domain, the R1628P mutation didn't alter the LRRK2 kinase activity and promote neuronal death directly. LRRK2 R1628P mutation increased the binding affinity of LRRK2 with Cyclin-dependent kinase 5 (Cdk5). Interestingly, R1628P mutation turned its adjacent amino acid residue S1627 on LRRK2 protein to a novel phosphorylation site of Cdk5, which could be defined as a typical type II (+) phosphorylation-related single nucleotide polymorphism. Importantly, we showed that the phosphorylation of S1627 by Cdk5 could activate the LRRK2 kinase, and neurons ectopically expressing R1628P displayed a higher sensitivity to 1-methyl-4-phenylpyridinium, a bioactive metabolite of environmental toxin MPTP, in a Cdk5-dependent manner.

Conclusion: Our data indicate that Parkinson-related LRRK2 mutation R1628P leads to Cdk5 phosphorylation of LRRK2 at S1627, which would upregulate the kinase activity of LRRK2 and consequently cause neuronal death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / pharmacology
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase 5 / genetics*
  • Cyclin-Dependent Kinase 5 / metabolism
  • HEK293 Cells
  • Herbicides / pharmacology
  • Humans
  • Immunoblotting
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation, Missense*
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics*
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Serine / genetics
  • Serine / metabolism
  • Up-Regulation

Substances

  • Herbicides
  • Serine
  • Cyclin-Dependent Kinase 5
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • 1-Methyl-4-phenylpyridinium

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 31071208, 31371384), Program for New Century Excellent Talents in University (No. NCET-10-0415), Doctor Startup Fund Program (JDFYRC-2015005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.