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dc.contributor.authorRuiz, Montserrat
dc.contributor.authorJové Font, Mariona
dc.contributor.authorSchlüter, Agatha
dc.contributor.authorCasasnovas, Carlos
dc.contributor.authorVillarroya, Francesc
dc.contributor.authorGuilera, Cristina
dc.contributor.authorOrtega, Francisco J.
dc.contributor.authorNaudí i Farré, Alba
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorGimeno, Ramón
dc.contributor.authorFourcade, Stéphane
dc.contributor.authorPortero Otín, Manuel
dc.contributor.authorPujol, Aurora
dc.date.accessioned2016-11-08T10:48:16Z
dc.date.issued2015
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/10459.1/58423
dc.description.abstractX-linked adrenomyeloneuropathy (AMN) is an inherited neurometabolic disorder caused by malfunction of the ABCD1 gene, characterized by slowly progressing spastic paraplegia affecting corticospinal tracts, and adrenal insufficiency. AMN is the most common phenotypic manifestation of adrenoleukodystrophy (X-ALD). In some cases, an inflammatory cerebral demyelination occurs associated to poor prognosis in cerebral AMN (cAMN). Though ABCD1 codes for a peroxisomal transporter of very long-chain fatty acids, the molecular mechanisms that govern disease onset and progression, or its transformation to a cerebral, inflammatory demyelinating form, remain largely unknown. Here we used an integrated -omics approach to identify novel biomarkers and altered network dynamic characteristic of, and possibly driving, the disease. We combined an untargeted metabolome assay of plasma and peripheral blood mononuclear cells (PBMC) of AMN patients, which used liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), with a functional genomics analysis of spinal cords of Abcd1− mouse. The results uncovered altered nodes in lipid-driven proinflammatory cascades, such as glycosphingolipid and glycerophospholipid synthesis, governed by the β-1,4-galactosyltransferase (B4GALT6), the phospholipase 2γ (PLA2G4C) and the choline/ethanolamine phosphotransferase (CEPT1) enzymes. Confirmatory investigations revealed a non-classic, inflammatory profile, consisting on the one hand of raised plasma levels of several eicosanoids derived from arachidonic acid through PLA2G4C activity, together with also the proinflammatory cytokines IL6, IL8, MCP-1 and tumor necrosis factor-α. In contrast, we detected a more protective, Th2-shifted response in PBMC. Thus, our findings illustrate a previously unreported connection between ABCD1 dysfunction, glyco- and glycerolipid-driven inflammatory signaling and a fine-tuned inflammatory response underlying a disease considered non-inflammatory.ca_ES
dc.description.sponsorshipWe are indebted to Dr Arndt G. Benecke for critically reading the manuscript. This study was supported by grants from the Hesperia Foundation, the Asociación Española contra las Leucodistrofias (ALE-ELA España), the Spanish Ministry for Health and Social Policy (MSPSI EC10-137), the European Commission (FP7- 241622), the Spanish Institute for Health Carlos III and ‘Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, una manera de hacer Europa’ (FIS PI11/01043, FIS PI14/00410, FIS ICI14/00076), and the Autonomous Government of Catalonia AGAUR (2009SGR85, 2014SGR1430 to A.P.); the Spanish Institute for Health Carlos III and ‘Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, una manera de hacer Europa’ (FIS PI14/ 00581) to C.C. and the Spanish Institute for Health Carlos III Miguel Servet program CP11/00080 to S.F. The studies conducted at the Department of Experimental Medicine were supported in part by R+D grants from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), the Spanish Ministry of Health (PI111543; PI1300584, PI140115), the Autonomous Government of Catalonia (2009SGR735), the ‘La Caixa’ Foundation, and COST B35 The CIBER on Rare Diseases (CIBERER) and on Physiopathology of Obesity and Nutrition (CIBEROBN) are initiatives of the ISCIII.ca_ES
dc.language.isoengca_ES
dc.publisherOxford University Pressca_ES
dc.relationMICINN/PN2008-2011/BFU2009-11879
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1093/hmg/ddv375ca_ES
dc.relation.ispartofHuman Molecular Genetics, 2015, vol. 24, núm. 24, p. 6861-6876ca_ES
dc.rights(c) Oxford University Press, 2015ca_ES
dc.titleAltered glycolipid and glycerophospholipid signaling drive inflammatory cascades in adrenomyeloneuropathyca_ES
dc.typearticleca_ES
dc.identifier.idgrec023429
dc.type.versionpublishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_ES
dc.identifier.doihttps://doi.org/10.1093/hmg/ddv375
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/241622
dc.date.embargoEndDate10000-01-01


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