Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
Exp Mol Pathol. 2014 Apr;96(2):139-48. doi: 10.1016/j.yexmp.2013.12.010. Epub 2014 Jan 5.
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.
SIRT1 是组蛋白去乙酰化酶 (HDAC) 家族 III 类蛋白的成员，是一种 NAD 依赖性组蛋白和蛋白质去乙酰化酶。SIRT1 可以通过组蛋白的去乙酰化诱导染色质沉默，并通过调节转录活性来调节细胞存活。我们研究了 SIRT1 在多发性硬化症 (MS) 大脑和复发性多发性硬化症患者外周血单核细胞 (PBMC) 中的表达。我们发现 SIRT1 在急性和慢性活动病变中大量细胞中表达。我们还发现 MS 斑块中的 CD4(+)、CD68(+)、少突胶质细胞 (OLG) 和神经胶质纤维酸性蛋白 (GFAP)(+) 细胞与 SIRT1 共定位。我们的结果表明，与对照组和稳定 MS 患者相比，SIRT1 mRNA 和蛋白质表达在 PBMC 复发时显著降低。另一方面，在 MS 患者的复发期间，HDAC3 表达没有显著变化。SIRT1 表达与组蛋白 H3 赖氨酸 9 乙酰化 (H3K9ac) 和甲基化 (H3K9me2) 相关。RGC-32 沉默后 SIRT1 mRNA 表达显著降低，表明 RGC-32 在 SIRT1 表达调控中起作用。此外，我们研究了 SIRT1 在 FasL 表达中的作用，发现抑制 SIRT1 表达后 FasL 表达和细胞凋亡显著增加。我们的数据表明，SIRT1 可能是复发的生物标志物，也是 MS 治疗干预的潜在新靶点。
