Possible treatment target in myelin damage, inflammation pathway
Excess levels of an inflammation-driving signaling molecule are toxic to glia, nerve cells
Damage to the myelin sheath, a hallmark feature of multiple sclerosis (MS), leads to increased levels of fatty molecules called VLCFAs, which are converted by brain cells into an inflammation-driving signaling molecule called S1P, a study suggests.
The discovery of this novel molecular pathway may open up new avenues for treating MS and other neurological inflammatory diseases, according to the researchers.
“We are very excited by the potential clinical implications of this study in not just how we treat MS patients, but also for other neurodegenerative conditions that are associated with demyelination, disruptions in lipid metabolism, and neuroinflammation,” Hugo Bellen, DVM, PhD, a professor at Baylor College of Medicine and co-author of the study, said in a press release.
The study, “Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation,” was published in Cell Metabolism.
In multiple sclerosis, inflammation in the brain and spinal cord damages the myelin sheath, a covering around nerve fibers that helps nerve cells send electrical signals. The breakdown of myelin is known to cause nerve cell dysfunction and death, though the precise molecular mechanisms are not fully understood.
Myelin is mostly made of fatty molecules. A particular class of fat molecule called very long chain fatty acids (VLCFAs) are present at high levels in myelin. When myelin gets damaged or destroyed, these fatty molecules are released and may be taken up by glial cells, the “pit crew” of the nervous system, responsible for providing maintenance and support to neurons that send electric signals.
Experimenting with fruit flies, the researchers showed that when VLCFAs are taken up by glia, these fatty molecules enter into a molecular pathway that converts them into sphingosine-1-phosphate, or S1P. The researchers showed that abnormally high S1P levels were toxic to glia and nearby nerve cells.
“Our data clearly indicate that glial cells produce excess S1P when VLCFA levels are elevated,” the researchers said, noting that S1P “can be taken up by neurons to cause neuronal dysfunction.”
S1P is a signaling molecule known to participate in a diverse array of biological processes. Among its many jobs, S1P helps coordinate the movement and activity of certain immune cells by binding to specialized protein receptors on the cells.
Blocking S1P activity, reducing inflammatory cells
Several approved treatments for relapsing MS — including Gilenya (fingolimod), Mayzent (siponimod), Ponvory (ponesimod), and Zeposia (ozanimod) — work by blocking S1P receptors’ activity, which is thought to reduce the number of disease-driving inflammatory cells that get into the nervous system.
Treating flies with Gilenya substantially decreased the neurotoxic effects of elevated VLCFA levels, the researchers found to their surprise since flies weren’t known to possess a S1P receptor protein analogous to the human version.
Given that Gilenya is known to modulate immune activity in MS, the finding prompted the researchers to examine the immune effects of increased VLCFAs in more detail. They showed that, in the fly models, high levels of VLCFAs — and subsequent higher S1P production — activated a part of the fruit fly immune system called the IMD pathway.
“This is the first time this immune pathway has been shown to lead to neuroinflammation in adult fruit flies,” Bellen noted.
Flies usually use this pathway to fight off infections and parasites, but in the presence of high VLCFA levels, the pathway was activated to cause inflammatory nerve damage comparable to what happens in MS.
“We argue that neurological diseases in which myelin is broken down may cause inflammation by elevating S1P,” the scientists wrote, noting the pathway may be a viable target for potential therapies.
The researchers next employed a drug called bezafibrate that’s known to reduce VLCFA production as part of experiments with mice with experimental autoimmune encephalomyelitis (EAE), a common mouse model of MS. In Canada, bezafibrate is marketed under the name Bezalip, among others, to help control fat levels, but it’s not approved in the U.S.
Mice treated with bezafibrate before inducing EAE had less disease activity, including less severe motor symptoms and less inflammatory brain damage, the researchers found. In mice with established EAE, bezafibrate or Gilenya separately had a modest effect on disease activity, but using both medications in combination led to a stronger effect than either alone.
“When we administered bezafibrate along with fingolimod at the onset of symptoms, we saw a synergistic improvement in EAE-induced paralysis and motor performance, demyelination and neuronal loss. The combined effects of these drugs were significantly better than the effect of either drug alone in every parameter we tested – suggesting that a combined therapy will be more effective and offer better outcomes for MS patients,” said Hyunglok Chung, a study co-author at Baylor.
Gilenya is sold by Novartis, which was not involved with this study.
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