title: Synucleins Have Multiple Effects on Presynaptic Architecture.
abstract: Synucleins (α, β, γ-synuclein) are a family of abundant presynaptic proteins. α-Synuclein is causally linked to the pathogenesis of Parkinson's disease (PD). In an effort to define their physiological and pathological function or functions, we investigated the effects of deleting synucleins and overexpressing α-synuclein PD mutations, in mice, on synapse architecture using electron microscopy (EM) and cryoelectron tomography (cryo-ET). We show that synucleins are regulators of presynapse size and synaptic vesicle (SV) pool organization. Using cryo-ET, we observed that deletion of synucleins increases SV tethering to the active zone but decreases the inter-linking of SVs by short connectors. These ultrastructural changes were correlated with discrete protein phosphorylation changes in αβγ-synuclein-/- neurons. We also determined that α-synuclein PD mutants (PARK1/hA30P and PARK4/hα-syn) primarily affected presynaptic cytomatrix proximal to the active zone, congruent with previous findings that these PD mutations decrease neurotransmission. Collectively, our results suggest that synucleins are important orchestrators of presynaptic terminal topography.
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06536, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT 06536, USA.
authors.forename: Karina J
authors.initials: KJ
authors.lastname: Vargas
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Schrod
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06536, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT 06536, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Davis
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT 06536, USA; Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06510, USA; Howard Hughes Medical Institute, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Fernandez-Busnadiego
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT 06536, USA; Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Yumiko V
authors.initials: YV
authors.lastname: Taguchi
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Laugks
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: vladan@biochem.mpg.de.
authors.forename: Vladan
authors.initials: V
authors.lastname: Lucic
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06536, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT 06536, USA; Department of Neuroscience, Yale University, New Haven, CT 06519, USA. Electronic address: sreeganga.chandra@yale.edu.
authors.forename: Sreeganga S
authors.initials: SS
authors.lastname: Chandra
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D051843:Synucleins / Q000378:metabolism*
chemical_list: D051843:Synucleins
keywords: Parkinson’s disease; amphiphysin; calcineurin; endocytosis; knockout mouse; presynaptic; reserve pool; synaptic vesicle; tethering; tomography