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 - 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 -