TY - JOUR
T1 - α-Synuclein multimers cluster synaptic vesicles and attenuate recycling
AU - Wang, Lina
AU - Das, Utpal
AU - Scott, David A.
AU - Tang, Yong
AU - McLean, Pamela J.
AU - Roy, Subhojit
N1 - Funding Information:
We thank Julia George (University of London) for the original TsixK plasmid; Shelley Halpain and Barbara Calabrese (UCSD) for the mRFP:Actin construct; Timothy Ryan (Weill Cornell) for pHluorin constructs and technical advice; and Tim Bartels and Dennis Selkoe (Harvard) for the 2F12 antibody. We also thank Virginia Lee (University of Pennsylvania), Leon Laganado (MRC, Cambridge), and Christoph Kaether (Leibniz Institute, Jena) for the guinea pig synuclein antibody, synaptophysin:mRFP, and synaptophysin:GFP constructs, respectively. This work was supported by grants to S.R. (P50AG005131—project 2, NIH) and P.J.M. (RO1 NS073740, NIH).
Publisher Copyright:
© 2014 Elsevier Ltd All rights reserved.
PY - 2014/10/6
Y1 - 2014/10/6
N2 - 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 [1, 2]; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer [3-8]. 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.
AB - 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 [1, 2]; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer [3-8]. 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.
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U2 - 10.1016/j.cub.2014.08.027
DO - 10.1016/j.cub.2014.08.027
M3 - Article
C2 - 25264250
AN - SCOPUS:84908221942
SN - 0960-9822
VL - 24
SP - 2319
EP - 2326
JO - Current Biology
JF - Current Biology
IS - 19
ER -