SIRT1 as a Potential Marker of Disease Activity and Response to Treatment with Glatiramer Acetate in Multiple Sclerosis
SIRT1 is a member of the histone deacetylase class III family of proteins and is a NAD-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through histone deacetylation and can modulate cell survival by regulating transcriptional activities. We have previously shown that SIRT1 mRNA expression was significantly lower in the peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in the PBMCs of stable patients.
Our goal was to longitudinally investigate the roles of SIRT1 expression as a possible biomarker of relapse and predictor of response to glatiramer acetate (GA) treatment in relapsing remitting (RR) MS. We also want to further investigate the downstream effects of SIRT1 expression by measuring its effects on acetylation (ac) and methylation (me2) of Histone H3 Lysine 9 (H3K9).
Over the course of 2 years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale, and blood samples were collected at 0, 3, 6, and 12 months. SIRT1 mRNA expression was measured in patients’ isolated PBMCs by real-time quantitative PCR. The levels of H3K9ac and H3K9me2 in conjunction with SIRT1 expression level were assessed by western blotting.
During relapses, MS patients had a decreased expression of SIRT1 mRNA (P<0.003) when compared to stable MS patients. Additionally, there was a significant decrease in H3K9me2 levels during relapse compared to stable patients (p<0.05). Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 compared to non-responders (p<0.04). SIRT1 protein expression was correlated with H3K9ac (r=0.5036, p<0.02) and H3K9me2 (r=0.4949, p<0.03) in non-responders to GA. Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 as a putative biomarker. The predictive values of relapse for SIRT1 mRNA was 72% (p<0.02). The predictive values of responsiveness to GA treatment were 70% (p=0.04) for SIRT1 mRNA.
Our data suggest that SIRT1 could serve as a potential biomarker in order to predict a MS relapse and evaluate a patients’ responsiveness to GA therapy. Such information could help improve treatment decisions in MS.