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LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Arranz, Amaia M., Delbroek, Lore, Van Kolen, Kristof, Guimarães, Marco R., Mandemakers, Wim, Daneels, Guy, Matta, Samer, Calafate, Sara, Shaban, Hamdy, Baatsen, Pieter, De Bock, Pieter-Jan, Gevaert, Kris, Vanden Berghe, Pieter, Verstreken, Patrik, De Strooper, Bart, Moechars, Diederik·2014·Journal of Cell Science

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 that may 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) 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.

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Metadata

Authors
Arranz, A. M., Delbroek, L., Van Kolen, K., Guimarães, M. R., Mandemakers, W., Daneels, G., Matta, S., Calafate, S., Shaban, H., Baatsen, P., De Bock, P.-J., Gevaert, K., Vanden Berghe, P., Verstreken, P., De Strooper, B., & Moechars, D.
Venue
Journal of Cell Science
Published
2014-01-01
ISSN
  • 1477-9137
  • 0021-9533
Cited by
111
References
1
Language
en

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