More than 1 million people across the United States live with multiple sclerosis (MS), a disease that affects the brain, optic nerves and spine. MS is an unpredictable disorder, with symptoms — such as overwhelming fatigue, muscle spasms and vision problems — flaring up and then subsiding over days, months or even years. To identify new treatment paradigms for MS, studying the underlying damage to the nervous system is key.
Katrina Adams , a neurobiologist at the University of Notre Dame, studies the role that the loss and regeneration of myelin plays in MS progression. A fatty substance that protects nerve cells, myelin envelopes the axons of the brain as they route the electrical signals that carry information throughout the nervous system, similar to how plastic insulation protects electrical wires. The damage and swelling that follow myelin loss in MS form distinct "lesions," which vary in size, number and location in the nervous system.
Because collecting viable tissue samples from patients with progressive disease is a challenge, scientists rely on preclinical biological models. A new study from the Adams research group, out today in Nature Communications , empirically compares for the first time two prevailing models — cuprizone (CPZ) and lysophosphatidylcholine (LPC) — for the study of myelin loss and regeneration in MS.
"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, who is the Gallagher Assistant Professor in the Department of Biological Sciences .
The CPZ and LPC paradigms are used largely interchangeably. But while both models degrade myelin, the timeline and localization of myelin loss varies between the two. CPZ causes widespread loss of myelin over several weeks. LPC, on the other hand, induces a lesion in just one place 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."
Beyond comparing CPZ and LPC to each other, Adams' team also analyzed the resulting lesions from each preclinical model alongside data obtained from human MS tissue samples. The researchers constructed genetic maps of each type of tissue with the help of single-cell RNA sequencing, allowing them 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.
"We were surprised to see several interesting genetic variations in some cell types, but we don't yet know if these changes encourage or discourage myelin regeneration," Adams said. "Learning more about these shifts in gene expression may reveal how MS affects the nervous system and how the body responds to it, which is essential groundwork for developing new therapies."
Since MS flare-ups are primarily triggered by the immune system's reaction to lesions — which also attacks healthy cells — current clinical treatments focus on quelling this autoimmune response. The regeneration of lost myelin within MS lesions, on the other hand, 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."
