Multiple sclerosis, a neuroinflammatory disease that affects nearly 3 million people worldwide, causes a loss of myelin, the fatty sheath that covers nerve cells in the brain and spinal cord.

Chronic loss of the protective myelin harms neurons. This damage leads to worsening disability in diseases such as MS that cause demyelination. However, it’s still unclear how this process causes neuron damage.

As described in a study published in Nature CommunicationsOregon Health & Science University researchers have developed new mouse models to confirm the link between failure to repair the protective covering around nerves and loss of neurons. They also identified a specific protein pathway that is related to the death of demyelinated nerve cells.

“Either by pharmacologically or genetically blocking this pathway, we could prevent the death of neurons in these chronically demyelinated mice,” said Ben Emery, Ph.D., corresponding author of the study. Emery is the Warren Distinguished Professor in Neuroscience Research and associate professor of neurology in the OHSU School of Medicine.

It is unclear why some humans’ myelin repairs itself faster than others. Myelin also repairs itself faster in mouse models than in humans, which is why the researchers genetically modified the mice to block remyelination and better mimic the pathology seen in human MS.

The researchers studied two types of mouse models that experience demyelination: one can repair itself, or remyelination, while the other cannot and suffers from lasting loss of myelin, or demyelination. Both types of mice show damage to their nerve fibers, but the ones that can’t remyelinate have more neuron death and increased inflammation. In contrast, the mice that could repair that protective covering show less neuron death and better recovery. The study’s lead author, Gregory Duncan, Ph.D., a postdoctoral scholar in Emery’s lab, developed this mouse model and discovered this link between the protein pathway and neuron death.

“These genetic models that Greg’s really pioneered are going to be useful for not only our lab, but probably many others to test neuroprotective strategies in this ongoing work on MS and other demyelinating diseases,” Emery said.

Mice that can’t remyelinate also show increased activity of a specific protein pathway linked to the death of nerve cells. When researchers blocked this pathway, it prevented neuron death in the damaged mice. The mice that repaired their myelin did not turn on that specific pathway, showing a direct link between the pathway and long-term myelin loss.

“It might suggest that inhibiting this pathway could be beneficial in preventing neurodegeneration or slowing the progression of MS,” Duncan said. “We have to be cautious though because this specific pathway has many roles in development and regeneration so any therapeutics developed would need to be targeted to avoid side effects and still be useful.”

Duncan and Emery said the model developed in this study will pave the way for other researchers to discover more about this important, but still somewhat mysterious, process that damages nerve cells.