title: Brain endothelial dysfunction in cerebral adrenoleukodystrophy.
abstract: See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA feichler@partners.org.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Musolino
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA feichler@partners.org.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gong
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Juliet M T
authors.initials: JM
authors.lastname: Snyder
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jimenez
authors.affiliation: 3 Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.affiliation: 3 Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: 4 Hugo W Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.affiliation: 5 Department of Paediatric Haematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Grabowski
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 6 C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Florian S
authors.initials: FS
authors.lastname: Eichler
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D006720:Homozygote; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D018613:Microscopy, Confocal; D055806:Microvessels / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C115572:ABCD1 protein, human; C112986:AIF1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C107466:CLDN5 protein, human; D002135:Calcium-Binding Proteins; D062507:Claudin-5; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C573420:ICAM1 protein, human; C489427:MYC protein, human; D008840:Microfilament Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C569042:TJP1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D062826:Zonula Occludens-1 Protein; D018799:Intercellular Adhesion Molecule-1
keywords: blood–brain barrier; demyelination; genetics; leukodystrophy; neurodegeneration; neuroinflammation