title: Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism.
abstract: Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non-MS individuals (n = 9) using mass-spectrometry. We have used western-blot and analyzed cell culture to confirm pathogenic pathways suggested by mass-spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8-iso-prostaglandin F2α is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde-mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal-modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation-modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator-activated receptor γ (PPARγ). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS.
authors.affiliation: Department of Experimental Medicine, PCiTAL-Universitat de Lleida-IRBLLEIDA, Lleida, Spain.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gonzalo
authors.forename: Luis
authors.initials: L
authors.lastname: Brieva
authors.forename: Franz
authors.initials: F
authors.lastname: Tatzber
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.forename: Daniel
authors.initials: D
authors.lastname: Cacabelos
authors.forename: Anna
authors.initials: A
authors.lastname: Cassanyé
authors.forename: Lucia
authors.initials: L
authors.lastname: Lanau-Angulo
authors.forename: Jordi
authors.initials: J
authors.lastname: Boada
authors.forename: José C E
authors.initials: JC
authors.lastname: Serrano
authors.forename: Cristina
authors.initials: C
authors.lastname: González
authors.forename: Lourdes
authors.initials: L
authors.lastname: Hernández
authors.forename: Sílvia
authors.initials: S
authors.lastname: Peralta
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000134:cerebrospinal fluid; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D005227:Fatty Acids / Q000134:cerebrospinal fluid; D005260:Female; D006037:Glyoxal / Q000032:analysis / Q000134:cerebrospinal fluid; D006801:Humans; D015227:Lipid Peroxidation / Q000276:immunology / Q000502:physiology*; D008055:Lipids / Q000134:cerebrospinal fluid* / Q000276:immunology; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000134:cerebrospinal fluid; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D009088:Mucoproteins / Q000378:metabolism; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D050050:Protein Carbonylation / Q000502:physiology; D011765:Pyruvaldehyde / Q000032:analysis / Q000134:cerebrospinal fluid
chemical_list: D001323:Autoantibodies; D005227:Fatty Acids; D008055:Lipids; D008077:Lipoproteins, LDL; D009088:Mucoproteins; D047495:PPAR gamma; C010393:lysin, gastropoda; D008315:Malondialdehyde; D006037:Glyoxal; D011765:Pyruvaldehyde