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
Biomedical Institute for Multimorbidity, Hull York Medical School, University of Hull, Hull HU6 7RX, UK.
Discovery and Translational Science Department, Leeds Institute of Cardiovascular & Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
Cells. 2024 Dec 17;13(24):2089. doi: 10.3390/cells13242089.
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 (Ca)- and RhoA/ROCK-dependent and was inhibited by prostacyclin (PGI). Our data suggest that α-synuclein regulates platelet secretion by facilitating SNARE complex formation.
颗粒分泌是血小板的一项重要功能，不仅有助于止血，还对伤口愈合、炎症和动脉粥样硬化有作用。血小板的颗粒分泌至少部分是由可溶性N - 乙基马来酰亚胺敏感因子（NSF）附着蛋白受体（SNARE）复合物介导的颗粒融合所促进。虽然α-突触核蛋白是一种已知能调节其他细胞中SNARE复合物组装的蛋白质，但其在血小板功能中的作用仍知之甚少。在本研究中，我们使用α-突触核蛋白缺陷（）小鼠提供了证据，证明α-突触核蛋白对止血至关重要。α-突触核蛋白的基因缺失导致体外血小板聚集、分泌和黏附受损。体内止血模型显示，α-突触核蛋白小鼠的出血时间和活化部分凝血活酶时间（aPTT）延长。从机制上讲，血小板活化诱导α-突触核蛋白丝氨酸（ser）129磷酸化并重新定位于血小板膜，同时与VAMP 8、 syntaxin 4和syntaxin 11的结合增加。这种磷酸化是钙（Ca）和RhoA/ROCK依赖性的，并被前列环素（PGI）抑制。我们的数据表明，α-突触核蛋白通过促进SNARE复合物形成来调节血小板分泌。
