title: LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.
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.
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Samer
authors.initials: S
authors.lastname: Matta
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Kolen
authors.forename: Raquel
authors.initials: R
authors.lastname: da Cunha
authors.forename: Geert
authors.initials: G
authors.lastname: van den Bogaart
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Miskiewicz
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: De Bock
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Morais
authors.forename: Sven
authors.initials: S
authors.lastname: Vilain
authors.forename: Dominik
authors.initials: D
authors.lastname: Haddad
authors.forename: Lore
authors.initials: L
authors.lastname: Delbroek
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.forename: Lucía
authors.initials: L
authors.lastname: Chávez-Gutiérrez
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Guy
authors.initials: G
authors.lastname: Daneels
authors.forename: Eric
authors.initials: E
authors.lastname: Karran
authors.forename: Matthew
authors.initials: M
authors.lastname: Holt
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Diederik W
authors.initials: DW
authors.lastname: Moechars
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D006224:Cricetinae; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D013058:Mass Spectrometry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012694:Serine / Q000235:genetics / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D002966:Clathrin; D029721:Drosophila Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D012694:Serine; D000217:Acyltransferases; C456023:endophilin A, Drosophila; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D002118:Calcium