title: Inhibition of angiogenesis by β-galactosylceramidase deficiency in globoid cell leukodystrophy.
abstract: Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme β-galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post-natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine β-galactosylceramidase complementary DNA. Finally, RNA interference-mediated β-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that β-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy.
authors: Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy.
authors: Mirella
authors: M
authors: Belleri
authors: Roberto
authors: R
authors: Ronca
authors: Daniela
authors: D
authors: Coltrini
authors: Beatrice
authors: B
authors: Nico
authors: Domenico
authors: D
authors: Ribatti
authors: Pietro L
authors: PL
authors: Poliani
authors: Arianna
authors: A
authors: Giacomini
authors: Patrizia
authors: P
authors: Alessi
authors: Sergio
authors: S
authors: Marchesini
authors: Marta B
authors: MB
authors: Santos
authors: Ernesto R
authors: ER
authors: Bongarzone
authors: Marco
authors: M
authors: Presta
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000473:pathology / Q000648:ultrastructure; D001672:Biocompatible Materials; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000633:toxicity; D004195:Disease Models, Animal; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000633:toxicity; D007965:Leukodystrophy, Globoid Cell / Q000150:complications* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000473:pathology* / Q000517:prevention & control; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011509:Proteoglycans / Q000633:toxicity; D011609:Psychosine / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage; D013997:Time Factors; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001672:Biocompatible Materials; D003094:Collagen; D004338:Drug Combinations; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D011609:Psychosine; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D062826:Zonula Occludens-1 Protein; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C569043:Tjp1 protein, mouse; C485184:enhanced green fluorescent protein; C059485:matrigel
keywords: Krabbe disease; angiogenesis; neurodegeneration; psychosine; twitcher mice
references: J Neurosci Res. 2011 Mar;89(3):352-64
references: 21259322
references: Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
references: 16633338
references: Brain Res Dev Brain Res. 2000 Jan 3;119(1):139-53
references: 10648880
references: Arch Pathol Lab Med. 2012 Jul;136(7):709-10
references: 22742542
references: J Neurosci Res. 2009 Jun;87(8):1748-59
references: 19185028
references: Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):454-64
references: 9102163
references: Cent Nerv Syst Agents Med Chem. 2012 Mar;12(1):7-14
references: 22280405
references: Mol Pharmacol. 2005 May;67(5):1451-9
references: 15703378
references: J Neurochem. 1992 Aug;59(2):607-9
references: 1629732
references: Biochim Biophys Acta. 2006 Dec;1758(12):2057-79
references: 16854371
references: Biochem Biophys Res Commun. 1982 Dec 15;109(3):634-8
references: 7159437
references: J Vasc Res. 1997 Nov-Dec;34(6):455-63
references: 9425998
references: J Neurosci Res. 2004 Aug 15;77(4):507-16
references: 15264220
references: Nat Rev Neurosci. 2008 Mar;9(3):169-81
references: 18253131
references: Trends Neurosci. 2005 Apr;28(4):202-8
references: 15808355
references: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9674-8
references: 9275182
references: PLoS One. 2012;7(7):e39598
references: 22792182
references: Glia. 2003 May;42(3):235-51
references: 12673830
references: Adv Exp Med Biol. 1980;131:69-78
references: 6108055
references: Acta Neuropathol. 1994;87(5):469-80
references: 8059599
references: Neurosci Lett. 2002 Sep 20;330(2):183-7
references: 12231442
references: J Neuropathol Exp Neurol. 2012 Nov;71(11):983-99
references: 23037326
references: Neurochem Res. 1998 Mar;23(3):251-9
references: 9482237
references: Arch Biochem Biophys. 2008 Sep 15;477(2):211-8
references: 18602885
references: Biochim Biophys Acta. 2002 May 23;1582(1-3):138-43
references: 12069821
references: J Neurosci. 2007 Dec 12;27(50):13730-8
references: 18077684
references: Brain Res Dev Brain Res. 1997 May 20;100(1):52-61
references: 9174246
references: Nature. 2011 May 19;473(7347):298-307
references: 21593862
references: J Lipid Res. 1980 Jan;21(1):53-64
references: 7354254
references: FEBS J. 2009 Sep;276(17):4622-35
references: 19664072
references: Cell. 2005 May 6;121(3):451-63
references: 15882626
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10623-8
references: 12963823
references: J Biol Chem. 2006 Sep 29;281(39):29190-200
references: 16891661
references: J Cell Biol. 2001 Apr 16;153(2):429-34
references: 11309421
references: Development. 1992 Feb;114(2):521-32
references: 1592003
references: Glia. 2013 May;61(5):765-77
references: 23404611
references: Brain Pathol. 1995 Jul;5(3):249-58
references: 8520724
references: J Neurochem. 2003 Sep;86(6):1428-40
references: 12950451
references: ASN Neuro. 2011;3(4):
references: 21929508
references: Clin Chim Acta. 2013 Apr 18;419:73-6
references: 23419961
references: Proc Natl Acad Sci U S A. 1970 Jun;66(2):302-9
references: 5271165
references: J Child Neurol. 2003 Sep;18(9):595-603
references: 14572137
references: Arterioscler Thromb Vasc Biol. 1997 Aug;17(8):1599-604
references: 9301641
references: J Neurosci. 2009 May 13;29(19):6068-77
references: 19439584
references: Neurochem Res. 2011 Sep;36(9):1612-22
references: 21136152
references: Acta Neuropathol. 2011 Jul;122(1):35-48
references: 21373782
references: Lab Invest. 1984 Jan;50(1):42-50
references: 6319815
references: Pediatr Neurol. 1991 Jan-Feb;7(1):18-22
references: 2029288
references: Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):601-8
references: 20441793
references: Neurosci Lett. 2004 Apr 1;358(3):205-9
references: 15039117
references: J Lipid Res. 2001 Dec;42(12):2092-5
references: 11734583
references: Neurobiol Dis. 2012 May;46(2):325-35
references: 22326830
references: Mol Cancer Ther. 2010 Dec;9(12):3244-53
references: 20940322
references: Chem Phys Lipids. 1990 Mar;53(2-3):165-75
references: 1970953
references: PLoS One. 2010 Sep 29;5(9):
references: 20927366
references: J Cell Biol. 2000 May 15;149(4):943-50
references: 10811833
references: Nature. 2005 Dec 15;438(7070):954-9
references: 16355213
references: Brain Dev. 2009 Aug;31(7):485-7
references: 19332366
references: Mol Genet Metab. 2000 May;70(1):1-9
references: 10833326
references: Biochem Biophys Res Commun. 1987 Apr 14;144(1):41-6
references: 3579916
references: Cell Growth Differ. 1996 Feb;7(2):147-60
references: 8822198
references: Trends Mol Med. 2009 Oct;15(10):439-51
references: 19801203
references: Blood. 2010 Sep 16;116(11):1857-66
references: 20511539
references: Biochim Biophys Acta. 2008 Mar;1780(3):370-82
references: 18077097
references: Neuropediatrics. 1985 Aug;16(3):137-42
references: 4047347
references: Clin Neuropathol. 1993 May-Jun;12(3):169-74
references: 8324966
references: J Neurochem. 1996 Mar;66(3):1118-24
references: 8769874
references: Nat Protoc. 2006;1(1):85-91
references: 17406216
references: Biochim Biophys Acta. 2009 Apr;1793(4):684-96
references: 19111581
references: Cancer Res. 1997 May 15;57(10):1829-34
references: 9157969
references: Brain Res. 1980 Dec 8;202(2):479-83
references: 7437911
references: Cancer Res. 1998 Oct 15;58(20):4510-4
references: 9788591
references: Angiogenesis. 2013 Apr;16(2):469-77
references: 23143707
references: Nat Methods. 2005 Apr;2(4):291-8
references: 15782212
references: Cancer Res. 2000 Mar 1;60(5):1388-93
references: 10728704
references: Science. 1984 May 18;224(4650):753-5
references: 6719111