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Updated: May 11, 2026

Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and
Jiajie Diao1, Jacqueline Burré, Sandro Vivona
1Department 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.
Abstract:
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 Ca(2+)-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. DOI:http://dx.doi.org/10.7554/eLife.00592.001.
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