title: LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism.
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.
authors.forename: Amaia M
authors.initials: AM
authors.lastname: Arranz
authors.forename: Lore
authors.initials: L
authors.lastname: Delbroek
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Kolen
authors.forename: Marco R
authors.initials: MR
authors.lastname: Guimarães
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.forename: Guy
authors.initials: G
authors.lastname: Daneels
authors.forename: Samer
authors.initials: S
authors.lastname: Matta
authors.forename: Sara
authors.initials: S
authors.lastname: Calafate
authors.forename: Hamdy
authors.initials: H
authors.lastname: Shaban
authors.forename: Pieter
authors.initials: P
authors.lastname: Baatsen
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: De Bock
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Pieter
authors.initials: P
authors.lastname: Vanden Berghe
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004331:Drosophila melanogaster; D034284:Dynamin I / Q000037:antagonists & inhibitors; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D006835:Hydrazones / Q000494:pharmacology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013395:Sucrose / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D013572:Synaptic Vesicles / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002966:Clathrin; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; C498434:Sh3gl2 protein, mouse; D013395:Sucrose; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D034284:Dynamin I