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: Kwang Soo Kim, Ji-Young Park, Ilo Jou, Sang Myun Park
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 28 Pg. 21416-25 (Jul 09 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20448034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein
• RALA protein, human
• ral GTP-Binding Proteins

Topics

• Alzheimer Disease (genetics)
• Cells, Cultured
• Endothelial Cells (metabolism)
• Endothelium, Vascular (cytology)
• Exocytosis
• Humans
• Microscopy, Confocal (methods)
• Microscopy, Immunoelectron (methods)
• Models, Biological
• Parkinson Disease (genetics)
• Point Mutation
• Protein Transport
• Weibel-Palade Bodies (metabolism)
• alpha-Synuclein (metabolism)
• ral GTP-Binding Proteins (metabolism)