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

  • Cell Rep. 2022 Apr 12;39(2):110675. doi: 10.1016/j.celrep.2022.110675.
Kathryn E Carnazza  1 ,  Lauren E Komer  1 ,  Ying Xue Xie  1 ,  André Pineda  1 ,  Juan Antonio Briano  1 ,  Virginia Gao  1 ,  Yoonmi Na  1 ,  Trudy Ramlall  2 ,  Vladimir L Buchman  3 ,  David Eliezer  2 ,  Manu Sharma  1 ,  Jacqueline Burré  4
Affiliations
  • 1. Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA.
  • 2. Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA.
  • 3. School of Biosciences, Cardiff University, Cardiff CF103AX, UK; Belgorod State National Research University, 85 Pobedy Street, Belgorod, Belgorod 308015, Russian Federation.
  • 4. Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: [email protected].
PMID: 35417693 DOI: 10.1016/j.celrep.2022.110675
Abstract

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.

Keywords
CP: Neuroscience; Parkinson’s disease; interaction; membrane binding; multimers; neurodegeneration; synapse; synaptic vesicle; synuclein; synucleinopathy.