SIRT1 is decreased during relapses in patients with multiple sclerosis

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• 作者：Cosmin A. Tegla^b ; ^a ; Philippe Azimzadeh^a ; Maria Andrian-Albescu^a ; Alvaro Martin^a ; Cornelia D. Cudrici^a ; Richard Trippe III^a ; Adam Sugarman^a ; Hegang Chen^d ; Dallas Boodhoo^a ; Sonia I. Vlaicu^a ; Walter Royal III^a ; ^e ; Christopher Bever^a ; ^b ; ^e ; Violeta Rus^c ; Horea Rus^a ; ^b ; ^e ; ^{hrus@umaryland.edu" class="auth_mail}
• 关键词：MS ; Multiple sclerosis ; RR ; Relapsing&ndash ; remitting ; HDAC3 ; Histone deacetylase 3 ; p-HDAC3 ; Phosphorylated histone deacetylase 3 ; SIRT1 ; Sirtuin 1 ; p-SIRT1 ; Phosphorylated sirtuin 1 ; EAE ; Experimental autoimmune encephalomyelitis ; TSA ; Trichostatin A ; CNS ; Central nervous system ; NAD ; Nicotinamide adenine dinucleotide ; NF-魏B ; Nuclear factor kappa-light-chain-enhancer of activated B cells ; FOXO ; Forkhead box gene ; PBMC ; Peripheral blood mononuclear cells ; FasL ; Fas Ligand ; RGC-32 ; Response gen
• 刊名：Experimental and Molecular Pathology
• 出版年：April, 2014
• 年：2014
• 卷：96
• 期：2
• 页码：139-148
• 全文大小：2091 K

文摘

SIRT1 is a member of the histone deacetylase (HDAC) class III family of proteins and is an NAD-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and can modulate cell survival by regulating the transcriptional activities. We investigated the expression of SIRT1 in multiple sclerosis (MS) brains and in peripheral blood mononuclear cells (PBMCs) obtained from patients with relapsing-remitting multiple sclerosis. We found that SIRT1 was expressed by a significant number of cells in both acute and chronic active lesions. We also found that CD4⁺, CD68⁺, oligodendrocytes (OLG), and glial fibrillar acidic protein (GFAP)⁺ cells in MS plaques co-localized with SIRT1. Our results show a statistically significant decrease in SIRT1 mRNA and protein expression in PBMCs during relapses when compared to the levels in controls and stable MS patients. On the other hand, HDAC3 expression was not significantly changed during relapses in MS patients. SIRT1 expression correlated with that of histone H3 lysine 9 acetylation (H3K9ac) and methylation (H3K9me2). SIRT1 mRNA expression was significantly reduced after RGC-32 silencing, indicating a role for RGC-32 in the regulation of SIRT1 expression. Furthermore, we investigated the role of SIRT1 in the expression of FasL and found a significant increase in FasL expression and apoptosis after inhibition of SIRT1 expression. Our data suggest that SIRT1 may represent a biomarker of relapses and a potential new target for therapeutic intervention in MS.