Chorein sensitivity of cytoskeletal organization and degranulation of platelets

• Published in: The FASEB journal Vol. 27; no. 7; p. 2799
• Main Authors: Schmidt, Eva-Maria, Schmid, Evi, Münzer, Patrick, Hermann, Andreas, Eyrich, Ann-Kathrin, Russo, Antonella, Walker, Britta, Gu, Shuchen, vom Hagen, Jennifer Müller, Faggio, Caterina, Schaller, Martin, Föller, Michael, Schöls, Ludger, Gawaz, Meinrad, Borst, Oliver, Storch, Alexander, Stournaras, Christos, Lang, Florian
• Format: Journal Article
• Language: English
• Published: United States 01.07.2013
• Subjects: Actins - metabolism; Adult; Blood Platelets - metabolism; Blood Platelets - physiology; Blood Platelets - ultrastructure; Blotting, Western; Cell Degranulation; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Cytoskeleton - metabolism; Female; Humans; Male; Microscopy, Confocal; Microscopy, Electron, Transmission; Middle Aged; Neuroacanthocytosis - blood; Neuroacanthocytosis - genetics; Neuroacanthocytosis - metabolism; p21-Activated Kinases - metabolism; Phosphorylation; Platelet Aggregation; R-SNARE Proteins - metabolism; RNA Interference; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Young Adult; VAMP8; aggregation; chorea-acanthocytosis; PI3K
• DOI: 10.1096/fj.13-229286

Chorea-acanthocytosis (ChAc), a lethal disease caused by defective chorein, is characterized by neurodegeneration and erythrocyte acanthocytosis. The functional significance of chorein in other cell types remained ill-defined. The present study revealed chorein expression in blood platelets. As compared to platelets from healthy volunteers, platelets from patients with ChAc displayed a 47% increased globular/filamentous actin ratio, indicating actin depolymerization. Moreover, phosphoinositide-3-kinase subunit p85 phosphorylation, p21 protein-activated kinase (PAK1) phosphorylation, as well as vesicle-associated membrane protein 8 (VAMP8) expression were significantly reduced in platelets from patients with ChAc (by 17, 22, and 39%, respectively) and in megakaryocytic (MEG-01) cells following chorein silencing (by 16, 54, and 11%, respectively). Activation-induced platelet secretion from dense granules (ATP release) and α granules (P-selectin exposure) were significantly less (by 55% after stimulation with 1 μg/ml CRP and by 33% after stimulation with 5 μM TRAP, respectively) in ChAc platelets than in control platelets. Furthermore, platelet aggregation following stimulation with different platelet agonists was significantly impaired. These observations reveal a completely novel function of chorein, i.e., regulation of secretion and aggregation of blood platelets.