title: α-synuclein multimers cluster synaptic vesicles and attenuate recycling.
abstract: The normal functions and pathologic facets of the small presynaptic protein α-synuclein (α-syn) are of exceptional interest. In previous studies, we found that α-syn attenuates synaptic exo/endocytosis; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer. However, conformations of α-syn at synapses--its physiologic locale--are unclear, and potential implications of such higher-order conformations to synaptic function are unknown. Exploring α-syn conformations and synaptic function in neurons, we found that α-syn promptly organizes into physiological multimers at synapses. Furthermore, our experiments indicate that α-syn multimers cluster synaptic vesicles and restrict their motility, suggesting a novel role for these higher-order structures. Supporting this, α-syn mutations that disrupt multimerization also fail to restrict synaptic vesicle motility or attenuate exo/endocytosis. We propose a model in which α-syn multimers cluster synaptic vesicles, restricting their trafficking and recycling, and consequently attenuate neurotransmitter release.
authors.affiliation: Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Utpal
authors.initials: U
authors.lastname: Das
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.affiliation: Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: s1roy@ucsd.edu.
authors.forename: Subhojit
authors.initials: S
authors.lastname: Roy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein