α-Synuclein is the major platelet isoform but is dispensable for activation, secretion, and thrombosis
Creators: name: Smith, Alexis N.
name: Joshi, Smita
name: Chanzu, Harry
name: Alfar, Hammodah R.
name: Prakhya, Kanakanagavalli Shravani
name: Whiteheart, Sidney W.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Neuroscience
subject: Physiology
subject: Hematology

description: Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via Soluble NSF Attachment Protein Receptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (<i>i.e</i>. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α-Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein’s role in platelet secretion is uncharacterized. In this study, immunofluorescence showed that α-synuclein was present on punctate structures that co-stained with markers for α-granules and lysosomes and in a cytoplasmic pool. We analyzed the phenotype of α-synuclein<sup>−/−</sup> mice and their platelets. Platelets from knockout mice had a mild, agonist-dependent secretion defect but aggregation and spreading <i>in vitro</i> were unaffected. Consistently, thrombosis/hemostasis were unaffected in the tail-bleeding, FeCl<sub>3</sub> carotid injury and jugular vein puncture models. None of the platelet secretory machinery examined, <i>e.g</i>. the v-SNAREs, were affected by α-synuclein’s loss. The results indicate that, despite its abundance, α-synuclein has only a limited role in platelet function and thrombosis. <b>What did we know?</b>The N-terminus of α-Synuclein affects SNARE-complex assembly, fusion pore opening, and granule docking.Microvascular bleeding is seen in Parkinson Disease patients where α-synuclein has a pathological role. The N-terminus of α-Synuclein affects SNARE-complex assembly, fusion pore opening, and granule docking. Microvascular bleeding is seen in Parkinson Disease patients where α-synuclein has a pathological role. <b>What did we discover?</b>α-Synuclein colocalizes with P-selectin (α-granules) and LAMP-1 (lysosomes) in platelets.The loss of α-synuclein has only a mild, agonist-dependent effect on platelet secretion.The loss of α-synuclein had no effect on thrombosis/hemostasis in 3 injury models. α-Synuclein colocalizes with P-selectin (α-granules) and LAMP-1 (lysosomes) in platelets. The loss of α-synuclein has only a mild, agonist-dependent effect on platelet secretion. The loss of α-synuclein had no effect on thrombosis/hemostasis in 3 injury models. <b>What is the impact?</b>Despite its abundance, α-synuclein is not required for platelet secretion.α-Synuclein is not required for hemostasis or thrombosis. Despite its abundance, α-synuclein is not required for platelet secretion. α-Synuclein is not required for hemostasis or thrombosis.