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; Buchman, Vladimir; Aburima, Ahmed

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.

Citation

Sennett, C., Jia, W., Khalil, J. S., Hindle, M. S., Coupland, C., Calaminus, S. D. J., Langer, J. D., Frost, S., Naseem, K. M., Rivero, F., Ninkina, N., Buchman, V., & Aburima, A. (2024). α-Synuclein Deletion Impairs Platelet Function: A Role for SNARE Complex Assembly. Cells, 13(24), Article 2089. https://doi.org/10.3390/cells13242089

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2024
• Online Publication Date: Dec 17, 2024
• Publication Date: Dec 2, 2024
• Deposit Date: Dec 18, 2024
• Publicly Available Date: Dec 20, 2024
• Journal: Cells
• Electronic ISSN: 2073-4409
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 24
• Article Number: 2089
• DOI: https://doi.org/10.3390/cells13242089
• Keywords: α-synuclein; Platelets; SNARE; Secretion
• Public URL: https://hull-repository.worktribe.com/output/4964729