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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

137 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 - 1 Feb 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015. Published by The Company of Biologists Ltd.

Funding
The research was supported by a research and development grant [grant number
100508] from the Agency for Innovation by Science and Technology
(IWT-Flanders); the European Research Council (ERC); the Fonds voor
Wetenschappelijk Onderzoek (FWO); the KULeuven; and Flemish Institute for
Biotechnology (VIB); and a Methusalem grant of the KULeuven/Flemish Government to B.D.S. B.D.S. is supported by the Bax-Vanluffelen chair for
Alzheimer’s Disease.

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