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Regulation of Weibel-Palade body exocytosis by alpha-synuclein in endothelial cells.

Authors
Kim, KS; Park, JY; Jou, I; Park, SM
Citation
The Journal of biological chemistry, 285(28):21416-21425, 2010
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
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.
MeSH terms
Alzheimer Disease/geneticsCells, CulturedEndothelial Cells/metabolism*Endothelium, Vascular/cytologyExocytosis*HumansMicroscopy, Confocal/methodsMicroscopy, Immunoelectron/methodsModels, BiologicalParkinson Disease/geneticsPoint MutationProtein TransportvWeibel-Palade Bodies/metabolism*alpha-Synuclein/metabolism*ral GTP-Binding Proteins/metabolism
DOI
10.1074/jbc.M110.103499
PMID
20448034
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
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