Brain endothelial dysfunction in cerebral adrenoleukodystrophy

Patricia L Musolino; Yi Gong; Juliet M T Snyder; Sandra Jimenez; Josephine Lok; Eng H Lo; Ann B Moser; Eric F Grabowski; Matthew P Frosch; Florian S Eichler

doi:10.1093/brain/awv250

Brain endothelial dysfunction in cerebral adrenoleukodystrophy

Brain. 2015 Nov;138(Pt 11):3206-20. doi: 10.1093/brain/awv250. Epub 2015 Sep 15.

Authors

Affiliations

¹ 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA [email protected].
² 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³ 3 Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
⁴ 4 Hugo W Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
⁵ 5 Department of Paediatric Haematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.
⁶ 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 6 C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
⁷ 1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 2 Center for Rare Neurological Diseases, Massachusetts General Hospital, Boston, MA, USA.

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.

Keywords: blood–brain barrier; demyelination; genetics; leukodystrophy; neurodegeneration; neuroinflammation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

ATP Binding Cassette Transporter, Subfamily D, Member 1
ATP-Binding Cassette Transporters / genetics*
Adolescent
Adrenoleukodystrophy / genetics*
Adrenoleukodystrophy / metabolism
Adrenoleukodystrophy / pathology
Adult
Aged
Aged, 80 and over
Blood-Brain Barrier / metabolism*
Brain / blood supply*
Brain / metabolism
Brain / pathology
Calcium-Binding Proteins
Case-Control Studies
Cells, Cultured
Child
Claudin-5 / genetics
Claudin-5 / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Demyelinating Diseases / metabolism*
Demyelinating Diseases / pathology
Endothelial Cells / metabolism
Endothelial Cells / pathology
Endothelium, Vascular / metabolism*
Endothelium, Vascular / pathology
Fatty Acids / metabolism
Female
Gene Knockdown Techniques
Heterozygote
Homozygote
Human Umbilical Vein Endothelial Cells
Humans
Intercellular Adhesion Molecule-1 / genetics
Intercellular Adhesion Molecule-1 / metabolism
Male
Microfilament Proteins
Microscopy, Confocal
Microvessels / cytology
Microvessels / metabolism*
Microvessels / pathology
Middle Aged
Multiple Sclerosis, Relapsing-Remitting / metabolism
Multiple Sclerosis, Relapsing-Remitting / pathology
Platelet Endothelial Cell Adhesion Molecule-1 / genetics
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Messenger / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Up-Regulation
Vascular Cell Adhesion Molecule-1 / genetics
Vascular Cell Adhesion Molecule-1 / metabolism
Young Adult
Zonula Occludens-1 Protein / genetics
Zonula Occludens-1 Protein / metabolism

Substances

ABCD1 protein, human
AIF1 protein, human
ATP Binding Cassette Transporter, Subfamily D, Member 1
ATP-Binding Cassette Transporters
CLDN5 protein, human
Calcium-Binding Proteins
Claudin-5
DNA-Binding Proteins
Fatty Acids
ICAM1 protein, human
MYC protein, human
Microfilament Proteins
Platelet Endothelial Cell Adhesion Molecule-1
Proto-Oncogene Proteins c-myc
RNA, Messenger
TJP1 protein, human
Vascular Cell Adhesion Molecule-1
Zonula Occludens-1 Protein
Intercellular Adhesion Molecule-1

Abstract

Publication types

MeSH terms

Substances

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