title: Chorein sensitivity of cytoskeletal organization and degranulation of platelets.
abstract: 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.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schmidt
authors.forename: Evi
authors.initials: E
authors.lastname: Schmid
authors.forename: Patrick
authors.initials: P
authors.lastname: Münzer
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eyrich
authors.forename: Antonella
authors.initials: A
authors.lastname: Russo
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.forename: Shuchen
authors.initials: S
authors.lastname: Gu
authors.forename: Jennifer Müller
authors.initials: JM
authors.lastname: vom Hagen
authors.forename: Caterina
authors.initials: C
authors.lastname: Faggio
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D015153:Blotting, Western; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D054546:Neuroacanthocytosis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation; D050683:R-SNARE Proteins / Q000378:metabolism; D034622:RNA Interference; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D050683:R-SNARE Proteins; C112938:VAMP8 protein, human; C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase; D054462:p21-Activated Kinases
keywords: PI3K; VAMP8; aggregation; chorea-acanthocytosis