Increased methionine sulfoxide levels in the CSF of multiple sclerosis patients

Zerina Balic, Fozia Mir, and Saud A. Sadiq, MD Presented at the American Academy of Neurology (AAN) 2017 Annual Meeting, held April 22-28, 2017 in Boston, Massachusetts

OBJECTIVE: To investigate the involvement of methionine oxidation in the pathophysiology of multiple sclerosis (MS). BACKGROUND: Methionine is an essential amino acid which is required for a number of metabolic process, such as protein synthesis, methylation, sulfur metabolism, redox regulation, and signal transduction. Methionine is highly susceptible to oxidation in vivo and the principal product of methionine oxidation is methionine sulfoxide (MetSO). Multiple studies have demonstrated that proteins lose their biological activity when specific methionine residues are oxidized to MetSO. In the current study we investigate the effect of methionine oxidation on pathogenesis in multiple sclerosis DESIGN/METHODS: Cerebrospinal fluid (CSF) was obtained from controls (n=30) and MS patients (n=120) with informed consent under an IRB-approved protocol. Samples were immediately processed and stored at -80 degree until use. Methionine metabolites were quantified by mass spectrometry (AbsoluteIDQ p180, Biocrates, Austria). MetSO levels were also measured by ELISA, using an anti-MetSO antibody. EAE was induced in C57BL/6J mice using MOG35-55 peptide. On day 14, at the peak of disease activity, the brain and spinal cord were removed for analysis. MetSO levels were measured by western blotting in whole brain and spinal cord lysates. RESULTS: Methionine sulfoxide levels were found to more than two fold elevated in the CSF of MS patients as compared to age- and sex-matched controls (p=0.017). Interestingly this increase in MetSO was more pronounced in the progressive MS patients (p=0.0003) and more modest in the relapsing remitting MS patients (p=0.02) as compared to the control population. These results were also confirmed by ELISA using an anti-protein MetSO antibody. Furthermore, we found that MetSO levels increased in the brain and spinal cord of mice during disease peak in EAE mice. CONCLUSIONS: These results show the dysregulation of methionine metabolic pathway during MS and may have effects of DNA methylation, myelin gene expression and anti-oxidant levels contributing to the pathophysiology.

Abstract Date

April 6, 2017

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