title: Regulation of Weibel-Palade body exocytosis by alpha-synuclein in endothelial cells.
abstract: alpha-Synuclein is a small presynaptic protein implicated in the pathogenesis of Parkinson disease. Nevertheless, its physiological roles and mechanisms remain incompletely understood. alpha-Synuclein is not only expressed in neurons but also in the vascular endothelium, which contains intracellular granules called Weibel-Palade bodies (WPBs) that contain a number of chemokines, adhesive molecules, and inflammatory cytokines. This study explored whether the exocytosis of WPB is regulated by alpha-synuclein. Phorbol 12-myristate 13-acetate-, thrombin-, or forskolin-induced von Willebrand factor release or translocation of P-selectin from endothelial cells were inhibited by alpha- and beta-synuclein but not gamma-synuclein. Three point mutants (A30P, A53T, and E46K) found in familial Parkinson disease also inhibited WPB exocytosis similar to that of wild-type alpha-synuclein. Furthermore, the negative regulation of WPB exocytosis required the N terminus or the nonamyloid beta-component of Alzheimer disease amyloid region of alpha-synuclein, but not the C-terminal acidic tail, and alpha-synuclein affected WPB exocytosis through interference with RalA activation by enhancing the interaction of RalGDS-beta-arrestin complexes. Immuno-EM analysis revealed that alpha-synuclein was localized close to WPBs. These findings imply that alpha-synuclein plays as a negative regulator in WPB exocytosis in endothelial cells.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon 442-721, Korea.
authors.forename: Kwang Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005089:Exocytosis; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008954:Models, Biological; D010300:Parkinson Disease / Q000235:genetics; D017354:Point Mutation; D021381:Protein Transport; D020302:Weibel-Palade Bodies / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D020725:ral GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
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