LRRK2 functions in synaptic vesicle endocytosis through a kinasedependent mechanism

Amaia M. Arranz, Lore Delbroek, Kristof van Kolen, Marco R. Guimarães, Wim Mandemakers, Guy Daneels, Samer Matta, Sara Calafate, Hamdy Shaban, Pieter Baatsen, Pieter Jan de Bock, Kris Gevaert, Pieter Vanden Berghe, Patrik Verstreken, Bart de Strooper, Diederik Moechars

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.

Original languageEnglish
Pages (from-to)541-552
Number of pages12
JournalJournal of Cell Science
Volume128
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

  • Endocytosis
  • Endophilin a1
  • LRRK2

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'LRRK2 functions in synaptic vesicle endocytosis through a kinasedependent mechanism'. Together they form a unique fingerprint.

Cite this