LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex

Maria D. Cirnaru, Antonella Marte, Elisa Belluzzi, Isabella Russo, Martina Gabrielli, Francesco Longo, Ludovico Arcuri, Luca Murru, Luigi Bubacco, Michela Matteoli, Ernesto Fedele, Carlo Sala, Maria Passafaro, Michele Morari, Elisa Greggio, Franco Onofri, Giovanni Piccoli

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex.

Original languageEnglish
Article number49
JournalFrontiers in Molecular Neuroscience
Volume7
Issue numberMAY
DOIs
Publication statusPublished - May 27 2014

Keywords

  • Kinase
  • LRRK2
  • Presynaptic vesicle
  • Protein interaction
  • Synaptic activity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology

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