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.
Keywords:
Krabbe disease; angiogenesis; neurodegeneration; psychosine; twitcher mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / metabolism
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Aorta / pathology
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Aorta / ultrastructure
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Biocompatible Materials
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Brain / drug effects
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Brain / pathology
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Brain / ultrastructure
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Cattle
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Cell Movement / drug effects
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Cell Movement / genetics
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Chorioallantoic Membrane / drug effects
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Chorioallantoic Membrane / metabolism
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Collagen / toxicity
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Disease Models, Animal
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Drug Combinations
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Green Fluorescent Proteins / metabolism
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Humans
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Laminin / toxicity
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Leukodystrophy, Globoid Cell / complications*
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Leukodystrophy, Globoid Cell / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Electron, Transmission
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Neovascularization, Pathologic / etiology*
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Neovascularization, Pathologic / pathology*
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Neovascularization, Pathologic / prevention & control
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Proteoglycans / toxicity
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Psychosine / metabolism
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Psychosine / pharmacology
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RNA, Small Interfering / administration & dosage
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Time Factors
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Transfection
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Umbilical Veins / cytology
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Zonula Occludens-1 Protein
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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Biocompatible Materials
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CD68 antigen, human
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Drug Combinations
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Laminin
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Platelet Endothelial Cell Adhesion Molecule-1
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Proteoglycans
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RNA, Small Interfering
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Tjp1 protein, mouse
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Vascular Endothelial Growth Factor A
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Zonula Occludens-1 Protein
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enhanced green fluorescent protein
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Fibroblast Growth Factor 2
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matrigel
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Green Fluorescent Proteins
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Psychosine
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Collagen
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Vascular Endothelial Growth Factor Receptor-2