Role of LRRK2 in the regulation of dopamine receptor trafficking

PLoS One. 2017 Jun 5;12(6):e0179082. doi: 10.1371/journal.pone.0179082. eCollection 2017.

Abstract

Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain. They differ in structural, pharmacological and biochemical properties, as well as in localization and internalization mechanisms. Our results indicate that disease-associated mutant G2019S LRRK2 impairs DRD1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect receptor turnover by decreasing the rate of DRD2 trafficking from the Golgi complex to the cell membrane. Collectively, our findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking. These findings have important implications for the complex role that LRRK2 plays in neuronal physiology and the possible pathological mechanisms that may lead to neuronal death in PD.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Golgi Apparatus / metabolism
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Protein Transport
  • Receptors, Dopamine D1 / genetics*
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics*
  • Receptors, Dopamine D2 / metabolism
  • Signal Transduction

Substances

  • DRD2 protein, mouse
  • Drd1 protein, mouse
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse

Grants and funding

This research was supported by Michael J. Fox Foundation (LRRK2 Challenge 2014 ID9550), Fondazione Banco di Sardegna (grant number 2014.0489) and Regione Sardegna (grant number CRP-78083) to CI and by Italian Ministry of Health (grant number RF-2011-02349806) to MM. MGDG was supported by a Post-doc fellowship of MJFF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.