Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis

Abstract

We have previously shown that SIRT1 mRNA expression was significantly lower in relapsing MS patients compared to those in remission. Our goal was to longitudinally investigate the role of active, phosphorylated SIRT1 (p-SIRT1) as a potential biomarker of relapse and predictor for response to glatiramer acetate (GA) treatment in patients with relapsing remitting multiple sclerosis (MS). We also want to investigate the downstream effects of SIRT1 activation by measuring the trimethylation of histone 3 at lysine 9 (H3K9me3). A cohort of 15 GA-treated patients was clinically monitored using the Expanded Disability Status Scale (EDSS) and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months after initiation of the therapy. P-SIRT1 and H3K9me3 levels were assayed by Western blotting using specific antibodies. Statistically significant lower levels of p-SIRT1 protein (p < 0.0001) and H3K9me3 (p = 0.001) were found during relapses when compared to stable MS patients. Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Statistically significant lower levels of p-SIRT1 protein (p = 0.02) and H3K9me3 (p = 0.004) were found in GA non-responders compared to responders. Using receiver operating characteristic analysis, area under the curve (AUC) for p-SIRT1 was 77% (p = 0.007) and for H3K9me3 was 81% (p = 0.002) for prediction of relapse. For predicting responsiveness to GA treatment, AUC was 75% (P = 0.01) for H3K9me3. Our data suggest that p-SIRT1 and H3K9me3 could serve as potential biomarkers for MS relapse. In addition, H3K9me3 could serve as possible biomarker to predict response to GA treatment.

Keywords: Biomarker; Glatiramer acetate; Histone trimethylation; Multiple sclerosis; PBMCs; SIRT1.