Synaptic vesicle binding of α-synuclein is modulated by β- and γ-synucleins

• Published in: Cell reports (Cambridge) 2022-04, Vol.39 (2), p.110675-110675, Article 110675
• Main Authors: Carnazza, Kathryn E., Komer, Lauren E., Xie, Ying Xue, Pineda, André, Briano, Juan Antonio, Gao, Virginia, Na, Yoonmi, Ramlall, Trudy, Buchman, Vladimir L., Eliezer, David, Sharma, Manu, Burré, Jacqueline
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; beta-Synuclein - metabolism; gamma-Synuclein - metabolism; interaction; membrane binding; Mice; multimers; neurodegeneration; Parkinson’s disease; Presynaptic Terminals - metabolism; synapse; synaptic vesicle; Synaptic Vesicles - metabolism; synuclein; synucleinopathy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110675

α-synuclein, β-synuclein, and γ-synuclein are abundantly expressed proteins in the vertebrate nervous system. α-synuclein functions in neurotransmitter release by binding to and clustering synaptic vesicles and chaperoning SNARE-complex assembly. Pathologically, aggregates originating from soluble pools of α-synuclein are deposited into Lewy bodies in Parkinson’s disease and related synucleinopathies. The functions of β-synuclein and γ-synuclein in presynaptic terminals remain poorly studied. Using in vitro liposome binding studies, circular dichroism spectroscopy, immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments on isolated synaptic vesicles in combination with subcellular fractionation of brains from synuclein mouse models, we show that β-synuclein and γ-synuclein have a reduced affinity toward synaptic vesicles compared with α-synuclein, and that heteromerization of β-synuclein or γ-synuclein with α-synuclein results in reduced synaptic vesicle binding of α-synuclein in a concentration-dependent manner. Our data suggest that β-synuclein and γ-synuclein are modulators of synaptic vesicle binding of α-synuclein and thereby reduce α-synuclein’s physiological activity at the neuronal synapse. [Display omitted] •β- and γ-synuclein have a reduced membrane affinity compared with α-synuclein•β- and γ-synuclein form heteromultimers with α-synuclein•Synuclein heteromerization reduces synaptic vesicle binding of α-synuclein α-synuclein functions in synaptic neurotransmitter release by binding to synaptic vesicles. The roles of β- and γ-synuclein in this process are unknown. Carnazza et al. demonstrate that on the synaptic vesicle surface, synucleins form heteromultimers whose composition dictates the amount of physiologically active α-synuclein on synaptic vesicles.