Multiple Sclerosis Myelin Loss Revealed by Transcriptomic Analysis in Mice

More than one million people across the United States live with multiple sclerosis (MS), a disease that affects the brain, optic nerves, and spine. MS is characterized by overwhelming fatigue, muscle spasms, and vision problems, which can flare up and then subside over days, months, or even years. Studying the underlying damage to the nervous system is key to identifying new treatment paradigms for MS. 

A new study published in Nature Communications titled, “A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions,” compares two prevailing models, cuprizone (CPZ) and lysophosphatidylcholine (LPC), for the study of myelin loss and regeneration in an MS mouse model. 

Katrina Adams, PhD, Gallagher Assistant Professor at University of Notre Dame, studies the role of the loss and regeneration of myelin on MS progression. As a fatty substance protects nerve cells, myelin envelopes the axons of the brain as they route the electrical signals that carry information throughout the nervous system. The damage and swelling that follow myelin loss in MS form distinct “lesions,” which vary in size, number and location in the nervous system. 

“Our analysis of these two models of myelin loss and regeneration provides a road map based on robust scientific evidence that we hope will advance the study of MS and related diseases,” said Adams. 

While both CPZ and LPC models degrade myelin, the timeline and localization of myelin loss varies. CPZ causes widespread loss of myelin over several weeks while LPC induces a lesion within days. This new research, which was funded by the National Multiple Sclerosis Society, points to specific scenarios in which one model is better suited, depending on which aspect of MS is under investigation. 

“If you’re studying the myelin-producing cells and what’s happening to them in MS—are they stressed, dying or trying to repair?—CPZ is better, since the loss of myelin is more gradual,” Adams said. “For studying the immune cells that respond to the myelin loss, LPC may be better, since the immune response is more aggressive than in CPZ.” 

The team also analyzed the resulting lesions from each preclinical model alongside data obtained from human MS tissue samples. Genetic maps of each type of tissue using single-cell RNA sequencing were constructed to examine the genetic changes that occurred in response to demyelination. 

“By matching each model to features seen in diseased tissue from real patients, we can be sure that we’re targeting things that are actually causing disease in human patients,” Adams said. “There are so many potential paths to follow, so we want to make sure that the path chosen has direct relevance to MS patients.” 

In addition to phenotypic differences, the genetic changes in diseased cells vary between the two models, an area of future exploration for the Adams research group. 

Since MS flare-ups are primarily triggered by the immune system’s reaction to lesions, current clinical treatments focus on quelling this autoimmune response. The regeneration of lost myelin within MS lesions remains a promising yet unrealized drug target. 

“The strategic use of these two preclinical models is essential for translating insights into therapies that might restore lost myelin,” Adams said. “We need to better understand the very process of demyelination in order to treat one of the root causes of this debilitating disorder.”