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-isoprostaglandin F2a 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 c (PPARc). 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. Keywords: autoimmunity, lipid peroxidation, PPAR, protein oxidation. J. Neurochem. (2012) 123, 622-634. Multiple sclerosis is a complex pathology belonging to the group of chronic inflammatory autoimmune diseases. Several risk factors have been defined for this disease such as genetic pre-disposition, dietary and other environmental factors such as obesity and smoking habit (recently reviewed in (Young 2011). Patients suffering from this disease have a spectrum of clinical manifestations, generally episodic, with frequent intervals of exacerbations followed by periods of remission.The ethiopathogeny of this disease comprises many aspects of immune system with dysfunctionality, including dearranged cytokine profile, T-cell population imbalance, abnormal presence of altered B cell and inmunoglobins in CNS, inappropriate activation of natural killer, dendritic cells and Received March 6, 2012; revised manuscript received August 18, 2012; accepted August 19, 2012. Address correspondence and reprint requests to Dr Manuel Portero-Otin, Universidad de Lleida c/Montserrat Roig 2, 25008 Lleida, Spain. E-mail: manuel.portero@mex.udl.catAbbreviations used: 2-PY, N1-methyl-2-pyridone-5-carboxamide; 8-iso-PGF2a, 8-iso-prostaglandin F2a; CML, carboxymethyl-lysine; HODE, hydroxyoctadecadienoic acid; LC, liquid chromatography;...

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