title: Synucleins regulate the kinetics of synaptic vesicle endocytosis.
abstract: Genetic and pathological studies link α-synuclein to the etiology of Parkinson's disease (PD), but the normal function of this presynaptic protein remains unknown. α-Synuclein, an acidic lipid binding protein, shares high sequence identity with β- and γ-synuclein. Previous studies have implicated synucleins in synaptic vesicle (SV) trafficking, although the precise site of synuclein action continues to be unclear. Here we show, using optical imaging, electron microscopy, and slice electrophysiology, that synucleins are required for the fast kinetics of SV endocytosis. Slowed endocytosis observed in synuclein null cultures can be rescued by individually expressing mouse α-, β-, or γ-synuclein, indicating they are functionally redundant. Through comparisons to dynamin knock-out synapses and biochemical experiments, we suggest that synucleins act at early steps of SV endocytosis. Our results categorize α-synuclein with other familial PD genes known to regulate SV endocytosis, implicating this pathway in PD.
authors.affiliation: Department of Neurology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut 06536.
authors.forename: Karina J
authors.initials: KJ
authors.lastname: Vargas
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Sachin
authors.initials: S
authors.lastname: Makani
authors.affiliation: Department of Neurology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut 06536.
authors.forename: Taylor
authors.initials: T
authors.lastname: Davis
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut 06536, Department of Cell Biology and.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Westphal
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.affiliation: Department of Neurology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, Connecticut 06536, Department of Molecular Cellular and Developmental Biology Yale University, New Haven, Connecticut 06519, and sreeganga.chandra@yale.edu.
authors.forename: Sreeganga S
authors.initials: SS
authors.lastname: Chandra
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000502:physiology* / Q000648:ultrastructure; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology*; D051843:Synucleins / Q000378:metabolism*
chemical_list: D051843:Synucleins
keywords: AP180; Parkinson's disease; endocytosis; membrane bending; presynaptic; synaptobrevin