title: α-Synuclein promotes dilation of the exocytotic fusion pore.
abstract: The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease. Like that of other proteins that accumulate in neurodegenerative disease, however, the function of α-synuclein remains unknown. Localization to the nerve terminal suggests a role in neurotransmitter release, and overexpression inhibits regulated exocytosis, but previous work has failed to identify a clear physiological defect in mice lacking all three synuclein isoforms. Using adrenal chromaffin cells and neurons, we now find that both overexpressed and endogenous synuclein accelerate the kinetics of individual exocytotic events, promoting cargo discharge and reducing pore closure ('kiss-and-run'). Thus, synuclein exerts dose-dependent effects on dilation of the exocytotic fusion pore. Remarkably, mutations that cause Parkinson's disease abrogate this property of α-synuclein without impairing its ability to inhibit exocytosis when overexpressed, indicating a selective defect in normal function.
authors.affiliation: Departments of Neurology and Physiology, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.|Graduate Program in Biomedical Sciences, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Logan
authors.affiliation: Departments of Neurology and Physiology, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Bendor
authors.affiliation: Departments of Neurology and Physiology, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Chantal
authors.initials: C
authors.lastname: Toupin
authors.affiliation: Department of Biochemistry &Biophysics, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kurt
authors.identifier: http://orcid.org/0000-0001-9310-288X
authors.initials: K
authors.lastname: Thorn
authors.affiliation: Departments of Neurology and Physiology, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.|Graduate Program in Biomedical Sciences, UCSF School of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000502:physiology; D004106:Dilatation; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D022142:Secretory Vesicles / Q000378:metabolism; D013572:Synaptic Vesicles / Q000502:physiology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D051844:alpha-Synuclein