title: Epigenetic modifications of Dexras 1 along the nNOS pathway in an animal model of multiple sclerosis.
abstract: The development of multiple sclerosis, a major neurodegenerative disease, is due to both genetic and environmental factors that might trigger aberrant epigenetic changes of the genome. In this study, we analysed global DNA methylation in the brain of mice upon induction of experimental autoimmune encephalomyelitis (EAE), and the effect of environmental enrichment (EE). We demonstrate that global DNA methylation decreased in the striatum, but not in the cortex, of EAE mice compared to healthy controls, in particular in neuronal nitric oxide synthase (nNOS)-positive interneurons of this brain area. Also, in the striatum but again not in the cortex, decreased DNA methylation of the nNOS downstream effector, dexamethasone-induced Ras protein 1 (Dexras 1), was observed in EAE mice, and was paralleled by an increase in its mRNA. Interestingly, EE was able to revert EAE effects on mRNA expression and DNA methylation levels of Dexras 1 and reduced gene expression of nNOS and 5-lipoxygenase (Alox5). Conversely, interleukin-1β (IL-1β) gene expression was found up-regulated in EAE mice compared to controls and was not affected by EE. Taken together, these data demonstrate an unprecedented epigenetic modulation of nNOS-signaling in the pathogenesis of multiple sclerosis, and show that EE can specifically revert EAE effects on Dexras 1 along this pathway.
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Catanzaro
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pucci
authors.affiliation: European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Viscomi
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Lanuti
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Feole
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Angeletti
authors.affiliation: European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Neurobiology, University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Grasselli
authors.affiliation: European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mandolesi
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Tor Vergata University of Rome, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bari
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy & IRCCS Neuromed, Pozzilli (IS), Italy.
authors.forename: D
authors.initials: D
authors.lastname: Centonze
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address: cdaddario@unite.it.
authors.forename: C
authors.initials: C
authors.lastname: D'Addario
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; European Center for Brain Research, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address: m.maccarrone@unicampus.it.
authors.forename: M
authors.initials: M
authors.lastname: Maccarrone
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009474:Neurons / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D044503:5-Methylcytosine; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D052248:Nitric Oxide Synthase Type I; C498511:Rasd1 protein, mouse; D018631:ras Proteins
keywords: DNA methylation; Dexras 1; Environmental enrichment; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Neuronal NOS