Epigenetic modifications of Dexras 1 along the nNOS pathway in an animal model of multiple sclerosis

Giuseppina Catanzaro, M. Pucci, M T Viscomi, M Lanuti, Monica Feole, S. Angeletti, G. Grasselli, G Mandolesi, M. Bari, D Centonze, Claudio D'Addario, M Maccarrone

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)32-40
Number of pages9
JournalJournal of Neuroimmunology
Volume294
DOIs
Publication statusPublished - May 15 2016

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ras Proteins
Nitric Oxide Synthase Type I
Autoimmune Experimental Encephalomyelitis
Epigenomics
Dexamethasone
Multiple Sclerosis
Animal Models
DNA Methylation
Gene Expression
Arachidonate 5-Lipoxygenase
Messenger RNA
Brain
Interneurons
Interleukin-1
Neurodegenerative Diseases
Genome

Keywords

  • Journal Article

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Epigenetic modifications of Dexras 1 along the nNOS pathway in an animal model of multiple sclerosis. / Catanzaro, Giuseppina; Pucci, M.; Viscomi, M T; Lanuti, M; Feole, Monica; Angeletti, S.; Grasselli, G.; Mandolesi, G; Bari, M.; Centonze, D; D'Addario, Claudio; Maccarrone, M.

In: Journal of Neuroimmunology, Vol. 294, 15.05.2016, p. 32-40.

Research output: Contribution to journalArticle

Catanzaro, Giuseppina ; Pucci, M. ; Viscomi, M T ; Lanuti, M ; Feole, Monica ; Angeletti, S. ; Grasselli, G. ; Mandolesi, G ; Bari, M. ; Centonze, D ; D'Addario, Claudio ; Maccarrone, M. / Epigenetic modifications of Dexras 1 along the nNOS pathway in an animal model of multiple sclerosis. In: Journal of Neuroimmunology. 2016 ; Vol. 294. pp. 32-40.
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AU - Catanzaro, Giuseppina

AU - Pucci, M.

AU - Viscomi, M T

AU - Lanuti, M

AU - Feole, Monica

AU - Angeletti, S.

AU - Grasselli, G.

AU - Mandolesi, G

AU - Bari, M.

AU - Centonze, D

AU - D'Addario, Claudio

AU - Maccarrone, M

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N2 - 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.

AB - 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.

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