title: SIRT1 is decreased during relapses in patients with multiple sclerosis.
abstract: 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.
authors.affiliation: Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Cosmin A
authors.initials: CA
authors.lastname: Tegla
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Azimzadeh
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Andrian-Albescu
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Cornelia D
authors.initials: CD
authors.lastname: Cudrici
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Trippe
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Sugarman
authors.affiliation: Department of Epidemiology and Public Health, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Hegang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Dallas
authors.initials: D
authors.lastname: Boodhoo
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Sonia I
authors.initials: SI
authors.lastname: Vlaicu
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Royal
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bever
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA. Electronic address: hrus@umaryland.edu.
authors.forename: Horea
authors.initials: H
authors.lastname: Rus
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D000099186:Histone Deacetylase 3
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D006655:Histone Deacetylases; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D056564:Sirtuin 1; D000099186:Histone Deacetylase 3; C115049:RGCC protein, human; C447939:SIRT1 protein, human
keywords: Acetylation; Biomarker; Epigenetics; HDAC3; Multiple sclerosis; Peripheral blood mononuclear cells; RGC-32; SIRT1