Regulation of Weibel-Palade Body Exocytosis by α-Synuclein in Endothelial Cells
Regulation of Weibel-Palade Body Exocytosis by α-Synuclein in Endothelial Cells
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DOI：
10.1074/jbc.m110.103499
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发表时间：
2010-07-09
影响因子：
4.8
通讯作者：
Park, Sang Myun
中科院分区：
文献类型：
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作者：
Kim, Kwang Soo;Park, Ji-Young;Park, Sang Myun
突触核蛋白是一种小的突触前蛋白，与帕金森病的发病机制有关。然而，其生理作用和机制尚不完全清楚。α -突触核蛋白不仅在神经元中表达，也在血管内皮中表达，血管内皮中含有称为韦贝尔-帕拉德体（webel - palade body, WPBs）的细胞内颗粒，其中含有许多趋化因子、粘附分子和炎症细胞因子。本研究探讨了α -突触核蛋白是否调控WPB的胞吐。α -突触核蛋白和α -突触核蛋白可抑制Phorbol 12-肉豆蔻酸13-醋酸酯、凝血酶或福斯克林诱导的血管性血变因子释放或p -选择素的易位，但α -突触核蛋白不能抑制。家族性帕金森病中发现的三个点突变体（A30P、A53T和E46K）也能抑制WPB胞分泌，与野生型α -突触核蛋白类似。此外，WPB胞外分泌的负调控需要α -突触核蛋白的N端或阿尔茨海默病淀粉样区非淀粉样β组分，而不需要c端酸性尾，α -突触核蛋白通过增强ralgds - β抑制蛋白复合物的相互作用，干扰RalA的激活，从而影响WPB胞外分泌。免疫电镜分析显示α -突触核蛋白定位在WPBs附近。这些发现提示-突触核蛋白在内皮细胞WPB胞吐中起负调节作用。
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 alpha-synuclein but not alpha-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.