title: Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms, whereas inflammation allegedly plays no role in AMN. How VLCFA accumulation leads to neurodegeneration and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. To gain insights into these questions, we undertook a transcriptomic approach followed by a functional-enrichment analysis in spinal cords of the animal model of AMN, the Abcd1(-) null mice, and in normal-appearing white matter of cAMN and cALD patients. We report that the mouse model shares with cAMN and cALD a common signature comprising dysregulation of oxidative phosphorylation, adipocytokine and insulin signaling pathways, and protein synthesis. Functional validation by quantitative polymerase chain reaction, western blots and assays in spinal cord organotypic cultures confirmed the interplay of these pathways through IkB kinase, being VLCFA in excess a causal, upstream trigger promoting the altered signature. We conclude that X-ALD is, in all its variants, a metabolic/inflammatory syndrome, which may offer new targets in X-ALD therapeutics.
authors.affiliation: Neurometabolic Diseases Laboratory and Institut de Neuropatologia de Bellvitge, L’Hospitalet de Llobregat, 08908 Barcelona, Spain.
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.forename: Lluís
authors.initials: L
authors.lastname: Espinosa
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Eva
authors.initials: E
authors.lastname: López
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Ilieva
authors.forename: Laia
authors.initials: L
authors.lastname: Morató
authors.forename: Muriel
authors.initials: M
authors.lastname: Asheuer
authors.forename: Ted
authors.initials: T
authors.lastname: Cook
authors.forename: Alistair
authors.initials: A
authors.lastname: McLaren
authors.forename: Juliet
authors.initials: J
authors.lastname: Reid
authors.forename: Fiona
authors.initials: F
authors.lastname: Kelly
authors.forename: Stewart
authors.initials: S
authors.lastname: Bates
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D054392:Adipokines / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000818:Animals; D053898:Biosynthetic Pathways; D001921:Brain / Q000378:metabolism*; D002648:Child; D004195:Disease Models, Animal; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D054392:Adipokines; D052242:Adiponectin; D005227:Fatty Acids; D007328:Insulin; D020738:Leptin; D016328:NF-kappa B; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9366-71
references.pmid: 9256488
references.citation: FASEB J. 2004 Jan;18(1):203-5
references.pmid: 14597556
references.citation: Diabetes. 2007 Aug;56(8):1986-98
references.pmid: 17519423
references.citation: J Clin Invest. 2006 Nov;116(11):3015-25
references.pmid: 17053832
references.citation: J Neuropathol Exp Neurol. 2000 Dec;59(12):1063-9
references.pmid: 11138926
references.citation: Biochem Biophys Res Commun. 2004 Oct 15;323(2):630-5
references.pmid: 15369797
references.citation: J Lipid Res. 2009 Jan;50(1):135-47
references.pmid: 18723473
references.citation: Hum Mol Genet. 2005 May 15;14(10):1293-303
references.pmid: 15800013
references.citation: Neuroreport. 2004 Jun 28;15(9):1427-30
references.pmid: 15194867
references.citation: Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):1040-52
references.pmid: 15998259
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Mol Cell Neurosci. 2006 Mar;31(3):427-37
references.pmid: 16337133
references.citation: Hum Mol Genet. 2008 Jun 15;17(12):1762-73
references.pmid: 18344354
references.citation: FEBS Lett. 2005 Dec 19;579(30):6821-6
references.pmid: 16325814
references.citation: Neurobiol Dis. 2003 Dec;14(3):425-39
references.pmid: 14678759
references.citation: Hum Mol Genet. 2004 Dec 1;13(23):2997-3006
references.pmid: 15489218
references.citation: Ann Neurol. 2004 Feb;55(2):221-35
references.pmid: 14755726
references.citation: Hum Mol Genet. 2002 Mar 1;11(5):499-505
references.pmid: 11875044
references.citation: J Neuropathol Exp Neurol. 2005 Dec;64(12):1067-79
references.pmid: 16319717
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6591-5
references.pmid: 8393571
references.citation: J Biol Chem. 2002 Jan 11;277(2):1531-7
references.pmid: 11606564
references.citation: Science. 2009 Nov 6;326(5954):818-23
references.pmid: 19892975
references.citation: Ann Neurol. 2011 Jul;70(1):84-92
references.pmid: 21786300
references.citation: Nat Rev Mol Cell Biol. 2008 Feb;9(2):162-76
references.pmid: 18216772
references.citation: Hum Mutat. 2001 Dec;18(6):499-515
references.pmid: 11748843
references.citation: Diabetes. 2005 Dec;54(12):3458-65
references.pmid: 16306362
references.citation: Diabetes. 1999 Jun;48(6):1270-4
references.pmid: 10342815
references.citation: J Biol Chem. 2002 Dec 13;277(50):48115-21
references.pmid: 12351658
references.citation: Brain Res Brain Res Protoc. 2002 Oct;10(2):60-8
references.pmid: 12431704
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Nat Genet. 2003 Jul;34(3):267-73
references.pmid: 12808457
references.citation: J Clin Invest. 1995 Sep;96(3):1455-63
references.pmid: 7657817
references.citation: FASEB J. 2006 Apr;20(6):750-2
references.pmid: 16464958
references.citation: Brain Pathol. 2010 Jul;20(4):838-44
references.pmid: 20626745
references.citation: Neuroscience. 2007 May 25;146(3):1182-92
references.pmid: 17395390
references.citation: FASEB J. 2008 Dec;22(12):4201-8
references.pmid: 18757502
references.citation: Nat Rev Immunol. 2006 Oct;6(10):772-83
references.pmid: 16998510
references.citation: Brain Pathol. 2010 Jul;20(4):857-62
references.pmid: 20626747
references.citation: Hum Mol Genet. 2008 Jun 15;17(12):1750-61
references.pmid: 18344355
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Eur J Pharmacol. 2008 May 6;585(1):176-96
references.pmid: 18378224
references.citation: Brain Pathol. 1998 Jan;8(1):101-20
references.pmid: 9458170
references.citation: Brain Pathol. 2010 Jul;20(4):817-30
references.pmid: 20626743
references.citation: Diabetes. 2006 Jan;55(1):141-7
references.pmid: 16380487
references.citation: J Neurosci. 2004 Sep 8;24(36):7779-88
references.pmid: 15356189
references.citation: Nature. 2004 Sep 9;431(7005):200-5
references.pmid: 15306821
references.citation: J Neurosci Res. 1997 Dec 1;50(5):829-43
references.pmid: 9418970
references.citation: J Immunol. 2011 Jun 15;186(12):7215-24
references.pmid: 21572034
references.citation: Nature. 1993 Feb 25;361(6414):726-30
references.pmid: 8441467
references.citation: Antioxid Redox Signal. 2011 Oct 15;15(8):2095-107
references.pmid: 21453200
references.citation: Acta Neuropathol. 1983;59(2):95-102
references.pmid: 6340408
references.citation: Ann Neurol. 2008 Jun;63(6):729-42
references.pmid: 18571777
references.citation: Hum Mol Genet. 2005 Dec 1;14(23):3565-77
references.pmid: 16223892