Functional and Pathological Effects of α-Synuclein on Synaptic SNARE Complexes.

TitleFunctional and Pathological Effects of α-Synuclein on Synaptic SNARE Complexes.
Publication TypeJournal Article
Year of Publication2023
AuthorsGao V, Briano JA, Komer LE, Burré J
JournalJ Mol Biol
Date Published2023 Jan 15
Keywordsalpha-Synuclein, Humans, Parkinson Disease, SNARE Proteins, Synapses, Synaptic Vesicles, Vesicle-Associated Membrane Protein 2

α-Synuclein is an abundant protein at the neuronal synapse that has been implicated in Parkinson's disease for over 25 years and characterizes the hallmark pathology of a group of neurodegenerative diseases now known as the synucleinopathies. Physiologically, α-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound α-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, α-synuclein functions in neurotransmitter release by modulating several steps in the synaptic vesicle cycle, including synaptic vesicle clustering and docking, SNARE complex assembly, and homeostasis of synaptic vesicle pools. These functions have been ascribed to α-synuclein's interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How α-synuclein affects these processes, and whether disease is due to loss-of-function or gain-of-toxic-function of α-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible reasons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature.

Alternate JournalJ Mol Biol
PubMed ID35787839
PubMed Central IDPMC10472340
Grant ListR01 NS113960 / NS / NINDS NIH HHS / United States
R01 NS121077 / NS / NINDS NIH HHS / United States
RF1 NS126342 / NS / NINDS NIH HHS / United States