Regulation of Weibel-Palade body exocytosis by alpha-synuclein in endothelial cells.
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.
Kim
Kwang Soo
KS
Department of Pharmacology, Ajou University School of Medicine, Suwon 442-721, Korea.
Park
Ji-Young
JY
Jou
Ilo
I
Park
Sang Myun
SM
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
D051844:alpha-Synuclein; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
Cell Mol Life Sci. 2000 Dec;57(13-14):1894-908
11215516
Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):899-904
11397694
Int J Biochem Cell Biol. 2009 Oct;41(10):2015-24
19460457
Am J Pathol. 2000 Aug;157(2):401-10
10934145
Thromb Haemost. 1997 Jun;77(6):1182-8
9241755
Genome Res. 1998 Sep;8(9):871-80
9750188
J Cell Biol. 2005 Jul 4;170(1):73-9
15998800
Blood. 2008 Jul 1;112(1):56-63
18417737
Blood. 2002 Oct 1;100(7):2506-14
12239163
Nat Cell Biol. 2002 Aug;4(8):547-55
12105416
Biochemistry. 1998 Apr 7;37(14):4901-9
9538008
Science. 1997 Jun 27;276(5321):2045-7
9197268
Neurosci Lett. 2002 Jun 21;326(1):5-8
12052525
Science. 2003 Oct 31;302(5646):841
14593171
Biochem Biophys Res Commun. 2009 Mar 27;381(1):39-43
19351591
Eur J Neurosci. 2000 Aug;12(8):3073-7
10971650
Br J Pharmacol. 2003 Apr;138(7):1191-201
12711617
Biochem Biophys Res Commun. 1997 Aug 28;237(3):611-6
9299413
J Biol Chem. 2008 Dec 12;283(50):35053-9
18948269
Trends Cardiovasc Med. 2005 Nov;15(8):302-8
16297768
J Biol Chem. 2002 Apr 5;277(14):12334-42
11821392
J Neurosci. 2006 Nov 15;26(46):11915-22
17108165
Nat Genet. 1998 Feb;18(2):106-8
9462735
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
15451224
Exp Neurol. 2000 Dec;166(2):324-33
11085897
J Neurosci. 2000 Aug 15;20(16):6048-54
10934254
Mol Cells. 2000 Feb 29;10(1):65-70
10774749
Neuron. 2000 Jan;25(1):239-52
10707987
Nat Struct Mol Biol. 2007 Oct;14(10):904-11
17891149
FEBS Lett. 2000 May 26;474(1):116-9
10828462
Neurosci Lett. 2000 Jun 16;287(1):65-7
10841992
Ann Neurol. 2004 Feb;55(2):164-73
14755719
J Cell Sci. 2002 Dec 1;115(Pt 23):4399-411
12414987
Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1315-20
15130921
Blood. 1982 Aug;60(2):531-4
6807373
J Neurosci. 2005 Jun 22;25(25):6016-24
15976091
Infect Immun. 2001 Dec;69(12):7820-31
11705964
J Neurosci. 2000 May 1;20(9):3214-20
10777786
FASEB J. 2003 Oct;17(13):1945-7
14519670
Arterioscler Thromb Vasc Biol. 2006 May;26(5):1002-7
16469951
Neurobiol Aging. 2008 Nov;29(11):1690-701
17537546
J Neurosci. 1999 Jul 15;19(14):5782-91
10407019
Acta Neurobiol Exp (Wars). 2008;68(4):509-15
19112474
Protein Sci. 2000 Dec;9(12):2489-96
11206070
Glia. 2008 Aug 15;56(11):1215-23
18449945
J Neurochem. 2006 Apr;97(1):265-79
16524375
Mol Cell Neurosci. 1999 Feb;13(2):95-103
10192768
Biochemistry. 2001 Sep 25;40(38):11604-13
11560511
Am J Pathol. 1998 Apr;152(4):879-84
9546347
Nat Med. 1998 Nov;4(11):1318-20
9809558
J Neurosci. 1988 Aug;8(8):2804-15
3411354
J Biol Chem. 1998 Apr 17;273(16):9443-9
9545270
FEBS Lett. 1998 Nov 27;440(1-2):71-5
9862428
Blood. 2009 Jan 22;113(4):973-80
18945966
Neurobiol Aging. 2008 May;29(5):739-52
17166628
J Clin Invest. 1987 Feb;79(2):600-8
3492515
J Biol Chem. 2001 Jul 20;276(29):27441-8
11316809
J Biol Chem. 2000 Aug 4;275(31):24065-9
10818098
Nature. 2000 Mar 23;404(6776):394-8
10746727