α-synuclein deletion impairs platelet function: A role for SNARE complex assembly

Sennett, Christopher, Jia, Wanzhu, Khalil, Jawad S., Hindle, Matthew S., Coupland, Charlie, Calaminus, Simon D. J., Langer, Julian D., Frost, Sean, Naseem, Khalid M., Rivero, Francisco, Ninkina, Natalia ORCID: https://orcid.org/0000-0001-8570-5648, Buchman, Vladimir ORCID: https://orcid.org/0000-0002-7631-8352 and Aburima, Ahmed 2024. α-synuclein deletion impairs platelet function: A role for SNARE complex assembly. Cells 13 (24) , 2089. 10.3390/cells13242089

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Abstract

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. Although α-synuclein is a protein known to modulate the assembly of the SNARE complex in other cells, its role in platelet function remains poorly understood. In this study, we provide evidence that α-synuclein is critical for haemostasis using α-synuclein-deficient (−/−) mice. The genetic deletion of α-synuclein resulted in impaired platelet aggregation, secretion, and adhesion in vitro. In vivo haemostasis models showed that α-synuclein−/− mice had prolonged bleeding times and activated partial thromboplastin times (aPTTs). Mechanistically, platelet activation induced α-synuclein serine (ser) 129 phosphorylation and re-localisation to the platelet membrane, accompanied by an increased association with VAMP 8, syntaxin 4, and syntaxin 11. This phosphorylation was calcium (Ca2+)- and RhoA/ROCK-dependent and was inhibited by prostacyclin (PGI2). Our data suggest that α-synuclein regulates platelet secretion by facilitating SNARE complex formation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	MDPI
ISSN:	2073-4409
Date of First Compliant Deposit:	6 January 2025
Date of Acceptance:	12 December 2024
Last Modified:	09 Jan 2025 12:31
URI:	https://orca.cardiff.ac.uk/id/eprint/175042

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