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.
In a study published Oct. 23 in Nature Communications, Oregon Health & Science University researchers 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 mice 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 remyelinate, 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 can 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.
In addition to Duncan and Emery, co-authors at OHSU include: Samantha Ingram, B.S., Katie Emberley, B.S., Jo Hill, M.S., Michael McCane, B.S., Skylar J. Ferrara, Ph.D., Brittany Stedelin, M.D., Benjamin Sivyer, Ph.D., Sue A. Aicher, Ph.D., Anusha Mishra, Ph.D., Jonathan W. Nelson, Ph.D., and Thomas S. Scanlan, Ph.D., as well as Christian Cordano, M.D., Ph.D., Ahmed Abdelhak, M.D., Nora Jabassini, B.S., Kirtana Ananth, B.S., Trent A. Watkins, Ph.D., and Ari J. Green, M.D., all with University of California San Francisco.
This work was supported by grants from Race to Erase MS, the NINDS (R01NS120981), NINDS P30 (NS061800), Collins Medical Trust (1016373), the National Multiple Sclerosis Society (RG-2001-35775), American Heart Association (20CDA35320169) and National Institute of Diabetes and Digestive and Kidney Diseases (K01DK121737). Duncan was supported by a postdoctoral fellowship (FG-1808-32238) and a career transition award (TA-2105-37636) from the National Multiple Sclerosis Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of any funders.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to this research project, Scanlan and Emery have significant interests in Autobahn Therapeutics, a company that may have a commercial interest in the results of this research and technology. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.
