For the first time, a new study empirically compares two prevailing models for the study of myelin loss and regeneration in multiple sclerosis. Researchers said their analysis of these models of myelin loss and regeneration will provide a road map, based on robust scientific evidence, which they hope will advance the study of MS.

More than 1 million people across the United States live with MS, a disease that affects the brain, optic nerves, and spine. MS is an unpredictable disorder, with symptoms — such as fatigue, muscle spasms, and vision problems — flaring up and then subsiding over days, months, or even years. Studying the underlying damage to the nervous system is key to identifying new treatment paradigms for MS.

Myelin, a fatty substance that protects nerve cells, envelopes the axons of the brain as they route electrical signals that carry information throughout the nervous system, similar to how plastic insulation protects electrical wires. The damage and swelling that follows myelin loss in MS forms 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. The cuprizone and lysophosphatidylcholine paradigms are used largely and 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, conducted by a University of Notre Dame research group, points to specific scenarios in which one model is better suited, depending on which aspect of MS is under investigation. According to the researchers, when studying the myelin-producing cells and what’s happening to them in MS — are they stressed, dying, or trying to repair — CPZ is better because the loss of myelin is more gradual. For studying the immune cells that respond to the myelin loss, LPC may be better, because the immune response is more aggressive than in CPZ.

Because 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 researchers said strategic use of these two preclinical models is essential for translating insights into therapies that might restore lost myelin A better understanding the very process of demyelination is needed to treat one of the root causes of this debilitating disorder.

Beyond comparing CPZ and LPC to each other, researchers 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.

In addition to phenotypic differences, the genetic changes in diseased cells vary between the two models — an area of future exploration for the research group. The researchers were surprised to see several interesting genetic variations in some cell types, but don’t know if these changes encourage or discourage myelin regeneration. 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.

The findings were published in the journal Nature Communications.