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

Kathryn E Carnazza | Lauren E Komer | Ying Xue Xie | André Pineda | Juan Antonio Briano | Virginia Gao | Yoonmi Na | Trudy Ramlall | Vladimir L Buchman | David Eliezer | Manu Sharma | Jacqueline Burré
Cell reports | 2022

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.

Pubmed ID: 35417693 RIS Download

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM136686
  • Agency: NINDS NIH HHS, United States
    Id: F31 NS125949
  • Agency: NIA NIH HHS, United States
    Id: R37 AG019391
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS102181
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS121077
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS113960
  • Agency: NIA NIH HHS, United States
    Id: R01 AG052505
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS095988

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