Methionine Metabolism Disrupted in MS


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Methionine Metabolism Disrupted in MS
Particularly impacted in progressive disease
  • by Kristina Fiore, Deputy Managing Editor, MedPage TodayNovember 14, 2017

WASHINGTON -- Metabolism of the essential amino acid methionine appears to be disrupted in multiple sclerosis, especially in progressive disease, researchers reported here.

Levels of methionine sulfoxide -- a product of methionine oxidation -- were elevated more than twofold in the cerebrospinal fluid of MS patients compared with that of matched controls (P=0.017), Fozia Mir, PhD, of the Tisch Research Center of New York, and colleagues reported during a poster session at the Society for Neuroscience meeting.

"In the CSF of MS patients, there's a huge increase in levels of methionine sulfoxide residues," Mir told MedPage Today. "It's very large and we see it throughout the spectrum of MS pathology. This seems to be something that we should be taking into consideration: why is methionine sulfoxide increased and what does it mean?"

Methionine is essential for several metabolic processes including protein synthesis, methylation, sulfur metabolism, redox regulation, and signal transduction, Mir said. It's highly susceptible to oxidation in vivo and the principal product of methionine oxidation is methionine sulfoxide. The consequence is that some proteins can lose their biological activity when incorporating methionine sulfoxide instead of methionine, she explained.

To get a better handle on methionine metabolism in MS, Mir and colleagues collected CSF samples from 120 MS patients and 30 age- and sex-matched controls. MS patients had relapsing-remitting, primary progressive, and secondary progressive disease.

In addition to finding elevated methionine sulfoxide levels in MS patients, they also saw that elevated levels of the compound were significantly more pronounced in progressive MS patients and were significantly increased -- but to a more modest extent -- in RRMS patients compared with controls.

In mice with experimental autoimmune encephalomyelitis, a standard animal model of MS, methionine sulfoxide levels were increased in brains and spinal cords at 14 days and at disease peak at 21 days. This elevation was accompanied by an increase in levels of methionine sulfoxide reductase-1 (MSR1) -- the enzyme that converts methionine sulfoxide back to methionine.

"There's a definite drop in MSR1 levels, so it seems as though this is important, but we're not sure if this is the only enzyme causing this effect," Mir said. "It may not be. There may be other mechanisms contributing to this."

Mir added that her work is focused on eventually finding treatments for progressive MS: "Neurologists tell us that they have good drugs for relapsing MS, that immune suppression works. We need to know about progression, because we don't really have anything there."

That's why her team is focused on metabolomic screening. "A metabolite is not a biomarker. It's indicative of something bigger," she said. "Looking at function is more crucial than saying, this is increased and it indicates progression. We can't deny that, but it's important to look beyond that."

While many clinicians feel they're stalling MS progression by treating the immune component of the disease with available therapies, she said, the fact that few treatments exist for progressive MS indicate "there is something that is totally independent of inflammation, and we should be looking at that too."