82. Chorein – connection between a neurodegenerative disease and platelet function

Abstract

Chorea-acanthocytosis (ChAc) is a lethal disease caused by defective chorein. The symptoms of the patients are characterized by hyperkinetic movement disorders with muscle dystrophy, cognitive dysfunction and behavioural abnormalities, hyperkalemia and acanthocytosis. Chorein affects the function of neurons, skeletal muscle and red blood cells. However, the functional significance of chorein in other cell types remains enigmatic. The present observation aimed to elucidate chorein-dependent mechanisms regulating platelet cytoskleleton structure and secretion in platelets from patients suffering from chorea-acanthocytosis. To determine the impact of chorein on platelet function, polymerization of actin, phosphorylation of PI3K-p85-subunit and PAK1 as well as VAMP8 expression were analyzed by western blotting. Activation induced P-selectin exposure and ATP release was measured by FACS and luciferase assay. As result, actin polymerization rate is diminished in platelets from ChAc patients compared to the platelets from healthy volunteers. Platelet analysis by electron microscopy revealed that structure of the actin cytoskeleton is drastically affected in platelets from ChAc patients. Moreover, PI3K-p85-subunit and PAK1 phosphorylation as well as VAMP8 expression were found to be significantly reduced in platelets from ChAc patients and in megakaryocytic cells following chorein silencing. Functionally, activation-induced platelet secretion from alpha granules and dense granules were significantly diminished in ChAc platelets than in control platelets. These observations revealed a completely novel function of chorein, especially regulation of cytoskeleton, PI3K signaling and secretion of blood platelets.