Study reveals biomarker, potentially improved therapy for MS

April 24, 2023
New research finds sphingosine-1-phosphate, produced by the degradation of myelin, results in neuroinflammation and drugs that reduce its level can reverse pathologies in animal models of multiple sclerosis.

Degeneration of myelin and neuroinflammation are notable hallmarks of MS. However, little is known about the precise molecular steps by which demyelination leads to the loss of neurons and glia, the two major types of brain cells.

The researchers at Texas Children’s Hospital and Baylor College of Medicine discovered that myelin breakdown results in an accumulation of very long-chain fatty acids and their intermediates, which triggers an autoimmune response that damages the brain cells. Furthermore, they showed that reducing the levels of VLCFA and S1P using known drugs, bezafibrate and fingolimod, had a synergistic beneficial effect on the MS pathologies in an animal model, revealing an even more effective treatment for MS patients.

Elevated levels of S1P are toxic to fly glia and neurons

A previous study showed that the loss of the fly version of the dACOX1 gene reduced the lifespan, caused neuronal and motor dysfunction, and eventually resulted in the demise of neurons and glia. The ACOX1 gene encodes an enzyme required for the breakdown of VLCFA. In this study, the researchers set out to understand the exact molecular steps by which the absence of dACOX1 results in the loss of neurons and glia.

VLFCA are a rare group of fatty acids that comprise only a tiny fraction of the total fatty acids in the body. Myelin sheaths that surround the nerve membranes are a rich source of VLCFAs and have roughly 10-fold higher levels of VLCFA-ceramides than other cellular membranes. VLCFA are produced from long-chain fatty acids by the ELOVL fatty acid elongase enzyme and converted back by the ACOX1 enzyme.

Researchers found the toxic effects observed because of the loss of dACOX1 could be suppressed by knocking down the gene that encodes ELOVL with Bezafibrate, a lipid-lowering drug. These observations further supported earlier observations that excess VLCFA is harmful to nerve cells.

The study’s authors next assessed how increased levels of VLCFA in the glia affected the metabolism of other lipids. They performed a mass spectrometric analysis of 26 lipids obtained from adult fly heads that lacked the fly version of the ACOX1 gene. They found two lipid intermediates – very long ceramides and sphingosine-1-phosphate – were significantly higher in the glia of these flies.

Further studies revealed that excess glial S1P was transported to the neurons and this increase in S1P levels was detrimental to the survival of both glia and neurons, and was sufficient to cause these cells to malfunction and degenerate. Notably, they found that supplementing dACOX1 mutant flies with fingolimod, an MS drug known to bind and downregulate S1P receptors levels, led to dramatic improvements in the overall viability, neuronal function, and importantly, delayed neurodegeneration in these flies.

Together, their data provide compelling evidence that the accumulation of S1P, a key product of VLCFA catabolism, is the root cause for the demise of glia and neurons in dACOX1 mutants.

S1P triggers strong immune responses that destroy brain cells in flies

The strong suppression of neurodegenerative symptoms in dACOX1 mutant flies by fingolimod, prompted the researchers to explore if elevated VLCFA had any effect on immune responses.

They observed that flies lacking ACOX1 had several large black, melanotic masses throughout their body including the head, eye, wing margins, and abdomen. The presence of melanotic masses in these flies suggested that the absence of dACOX1 induces an autoimmune response whereby the immune cells misinterpret the presence of an innocuous molecule as a sign of a cellular invasion and mount an unwarranted attack that destroys their own cells. They next asked if the loss of dACOX1 also activated other immune pathways.

Flies have two major immune pathways that control inducible immune responses to invading bacteria and fungi by systemic production of cytokines, and antimicrobial peptides upon activation of the nuclear factor-kB. Notably, the authors found that elevated S1P in fly glia activates NF-kB which in turn significantly increased the transcript levels of several AMP genes involved in the IMD pathway. Moreover, circulating immune cells are recruited to the central nervous system.

Bezafibrate and fingolimod ameliorate the progression of MS symptoms in mice

Excited by these findings, the team then explored the role of elevated VLCFA and S1P in MS progression in vertebrates by collaborating with researchers at Baylor. 

First, the researchers found that presymptomatic treatment of mice with bezafibrate, a lipid-lowering drug that inhibits the synthesis of VLCFA, slowed the progression of experimental autoimmune encephalomyelitis pathology by reducing demyelination, neuronal damage, and infiltration of immune cells into the brain. These results showed that this drug can slow the progression of this debilitating disorder.

They next tested the potential therapeutic effect of lowering VLCFA and S1P on MS. When they administered bezafibrate along with fingolimod at the onset of symptoms, they found 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 they tested – suggesting a combined therapy may be more effective and offer better outcomes for MS patients.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the study’s authors are very excited by the potential clinical implications of this study in not just how MS patients are treated but also for other neurodegenerative conditions that are linked to demyelination, disruptions in lipid metabolism, and neuroinflammation.

The paper was published in Cell Metabolism.

MS Focus Lending Library

Books, DVDs, and CDs are available for loan, by mail across the United States.
Learn more