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Title: LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis
Authors: Matta, Samer ×
Van Kolen, Kristof
da Cunha, Raquel
van den Bogaart, Geert
Mandemakers, Wim
Miskiewicz, Katarzyna
De Bock, Pieter-Jan
Morais, Vanessa
Vilain, Sven
Haddad, Dominik
Delbroek, Lore
Swerts, Jef
Chávez-Gutiérrez, Lucía
Esposito, Giovanni
Daneels, Guy
Karran, Eric
Holt, Matthew
Gevaert, Kris
Moechars, Diederik W
De Strooper, Bart
Verstreken, Patrik #
Issue Date: Sep-2012
Publisher: Cell Press
Series Title: Neuron vol:75 issue:6 pages:1008-1021
Article number: 10.1016/j.neuron.2012.08.022
Abstract: LRRK2 is a kinase mutated in Parkinson's disease, but how the protein affects synaptic function remains enigmatic. We identified LRRK2 as a critical regulator of EndophilinA. Using genetic and biochemical studies involving Lrrk loss-of-function mutants and Parkinson-related LRRK2(G2019S) gain-of-kinase function, we show that LRRK2 affects synaptic endocytosis by phosphorylating EndoA at S75, a residue in the BAR domain. We show that LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association in vitro and in vivo and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo. Our work uncovers a regulatory mechanism that indicates that reduced LRRK2 kinase activity facilitates EndoA membrane association, while increased kinase activity inhibits membrane association. Consequently, both too much and too little LRRK2-dependent EndoA phosphorylation impedes synaptic endocytosis, and we propose a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses.
ISSN: 0896-6273
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Neuronal Communication
Laboratory for the Research of Neurodegenerative Diseases
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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