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VAMP2 regulates phase separation of α-synuclein

Affiliations
  • 1Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 2Protein and Cellular Sciences, GSK, Stevenage, UK.
  • 3Department of Clinical Neurosciences, UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 4Wellcome Trust-Medical Research Council Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
  • 5Department of Haematology, University of Cambridge, School of Clinical Medicine, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
  • 6Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 7MRC Toxicology Unit, University of Cambridge, Cambridge, UK.
  • 8Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. janin.lautenschlaeger@gmail.com.

Published on:

July 1, 2024

Abstract

α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson’s disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology.

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