Exogenous human α-Synuclein acts in vitro as a mild platelet antiaggregant inhibiting α-thrombin-induced platelet activation
Abstract
alpha-Synuclein (alpha Syn) is a small disordered protein, highly conserved in vertebrates and involved in the pathogenesis of Parkinson's disease (PD). Indeed, alpha Syn amyloid aggregates are present in the brain of patients with PD. Although the pathogenic role of alpha Syn is widely accepted, the physiological function of this protein remains elusive. Beyond the central nervous system, alpha Syn is expressed in hematopoietic tissue and blood, where platelets are a major cellular host of alpha Syn. Platelets play a key role in hemostasis and are potently activated by thrombin (alpha T) through the cleavage of protease-activated receptors. Furthermore, both alpha T and alpha Syn could be found in the same spatial environment, i.e. the platelet membrane, as alpha T binds to and activates platelets that can release alpha Syn from alpha-granules and microvesicles. Here, we investigated the possibility that exogenous alpha Syn could interfere with platelet activation induced by different agonists in vitro. Data obtained from distinct experimental techniques (i.e. multiple electrode aggregometry, rotational thromboelastometry, immunofluorescence microscopy, surface plasmon resonance, and steady-state fluorescence spectroscopy) on whole blood and platelet-rich plasma indicate that exogenous alpha Syn has mild platelet antiaggregating properties in vitro, acting as a negative regulator of alpha T-mediated platelet activation by preferentially inhibiting P-selectin expression on platelet surface. We have also shown that both exogenous and endogenous (i.e. cytoplasmic) alpha Syn preferentially bind to the outer surface of activated platelets. Starting from these findings, a coherent model of the antiplatelet function of alpha Syn is proposed. Show more
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https://doi.org/10.3929/ethz-b-000554633Publication status
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Scientific ReportsVolume
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NatureMore
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