TY - JOUR
T1 - Epigenetic modifications of Dexras 1 along the nNOS pathway in an animal model of multiple sclerosis
AU - Catanzaro, G.
AU - Pucci, M.
AU - Viscomi, M. T.
AU - Lanuti, M.
AU - Feole, M.
AU - Angeletti, S.
AU - Grasselli, G.
AU - Mandolesi, G.
AU - Bari, M.
AU - Centonze, D.
AU - D'Addario, C.
AU - Maccarrone, M.
PY - 2016/5/15
Y1 - 2016/5/15
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.
KW - Dexras 1
KW - DNA methylation
KW - Environmental enrichment
KW - Experimental autoimmune encephalomyelitis
KW - Multiple sclerosis
KW - Neuronal NOS
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UR - http://www.scopus.com/inward/citedby.url?scp=84962376082&partnerID=8YFLogxK
U2 - 10.1016/j.jneuroim.2016.03.009
DO - 10.1016/j.jneuroim.2016.03.009
M3 - Article
AN - SCOPUS:84962376082
VL - 294
SP - 32
EP - 40
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
SN - 0165-5728
ER -