title: Altered glycolipid and glycerophospholipid signaling drive inflammatory cascades in adrenomyeloneuropathy.
abstract: X-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.
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER).
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Experimental Medicine Department, University of Lleida-IRBLleida, Lleida, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER).
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, c/ Feixa Llarga s/n, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Casasnovas
authors.affiliation: Center for Biomedical Research on Physiopathology of Obesity and Nutrition, ISCIII, Spain, Departament de Bioquimica i Biologia Molecular and Institut de Biomedicina IBUB, Universitat de Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER).
authors.forename: Cristina
authors.initials: C
authors.lastname: Guilera
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER).
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ortega
authors.affiliation: Experimental Medicine Department, University of Lleida-IRBLleida, Lleida, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.affiliation: Experimental Medicine Department, University of Lleida-IRBLleida, Lleida, Spain.
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.affiliation: Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain and.
authors.forename: Ramón
authors.initials: R
authors.lastname: Gimeno
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER).
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.affiliation: Experimental Medicine Department, University of Lleida-IRBLleida, Lleida, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER), Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain apujol@idibell.cat.
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; D000326:Adrenoleukodystrophy / Q000097:blood* / Q000235:genetics; D000328:Adult; D000818:Animals; D020404:Glycerophospholipids / Q000097:blood*; D006017:Glycolipids / Q000097:blood*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D020404:Glycerophospholipids; D006017:Glycolipids; D018836:Inflammation Mediators