Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2
Jiajie Diao,
Jacqueline Burré,
Sandro Vivona,
Daniel J Cipriano,
Manu Sharma,
Minjoung Kyoung,
Thomas C Südhof,
Axel T Brunger
Affiliations
Jiajie Diao
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States; Departments of Photon Sciences, and Neurology and Neurological Sciences, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Jacqueline Burré
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
Sandro Vivona
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States; Departments of Photon Sciences, and Neurology and Neurological Sciences, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Daniel J Cipriano
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States; Departments of Photon Sciences, and Neurology and Neurological Sciences, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Manu Sharma
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
Minjoung Kyoung
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States; Departments of Photon Sciences, and Neurology and Neurological Sciences, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Thomas C Südhof
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
Axel T Brunger
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States; Departments of Photon Sciences, and Neurology and Neurological Sciences, Stanford University, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
α-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native α-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native α-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native α-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native α-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of α-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. α-Synuclein had little effect on Ca2+-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. α-Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a ‘buffer’ of synaptic vesicles, without affecting neurotransmitter release itself.
