title: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
authors.affiliation: Department of Protein Science and Institute of Developmental Genetics, Helmholtz Zentrum München, D-85764 Munich, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piccoli
authors.forename: Steven B
authors.initials: SB
authors.lastname: Condliffe
authors.forename: Matthias
authors.initials: M
authors.lastname: Bauer
authors.forename: Florian
authors.initials: F
authors.lastname: Giesert
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.forename: Silvia
authors.initials: S
authors.lastname: De Astis
authors.forename: Andrea
authors.initials: A
authors.lastname: Meixner
authors.forename: Hakan
authors.initials: H
authors.lastname: Sarioglu
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Vogt-Weisenhorn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Christian Johannes
authors.initials: CJ
authors.lastname: Gloeckner
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000648:ultrastructure*; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000648:ultrastructure*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D013574:Synaptosomes / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D011189:Potassium Chloride; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D052066:N-Ethylmaleimide-Sensitive Proteins; C498733:Nsf protein, mouse; D002118:Calcium