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VAMP2 regulates phase separation of α-synuclein.

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.

SUBMITTER: Agarwal A

PROVIDER: S-EPMC11322000 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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VAMP2 regulates phase separation of α-synuclein.

Agarwal Aishwarya A Chandran Aswathy A Raza Farheen F Ungureanu Irina-Maria IM Hilcenko Christine C Stott Katherine K Bright Nicholas A NA Morone Nobuhiro N Warren Alan J AJ Lautenschläger Janin J

Nature cell biology 20240701 8

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 ...[more]

PMID: 38951707

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