CLEVELAND—A team of scientists led by the Institute for Glial Sciences (IGS) at Case Western Reserve University's School of Medicine has discovered a built-in "brake" that controls when key brain cells mature. In multiple sclerosis (MS), this brake appears to stay on too long, leaving the cells unable to repair the damage the disease causes.
The study, published today in the journal Cell , identifies a new framework for how cells control when they mature. The discovery also presents a potential regenerative medicine approach to repair the damage caused by MS and similar diseases affecting the nervous system.
"Myelin damage drives disability in MS, and the only cells that can repair it are glial cells called oligodendrocytes," said the study's senior author, Paul Tesar, director of the Institute for Glial Sciences and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics at the School of Medicine. "By identifying the molecular brake that controls when oligodendrocytes mature, we reveal a clear path to unlocking the brain's own repair program."
The team is now working to understand why this immature state is heightened in MS brains and whether this same framework operates in other cell types or contributes to stalled repair in other diseases.
"MS is a progressive disease that gets worse over time and patients still lack therapies that can restore the myelin they've lost," Tesar said. "We believe these new insights will help deliver on the promise of regenerative therapies that MS patients so urgently need."
The study focused on oligodendrocytes, which wrap neurons in protective myelin sheaths that are lost in MS. Oligodendrocytes belong to a category of cells known as glia, which comprise over half of the cells in our nervous system but have largely been overlooked by scientists in favor of neurons. The IGS was created last year at Case Western Reserve to understand how these vital cells function in health and disease.
To understand how oligodendrocytes acquire their ability to myelinate neurons, the IGS scientists tracked thousands of molecular changes as immature cells developed into mature, myelin-forming oligodendrocytes. One protein, called SOX6, stood out.
The team found that SOX6 acted like a brake, stalling cells in an immature state through a phenomenon known as "gene melting." This brake is essential in healthy brain development because it prevents premature myelin formation and ensures that oligodendrocytes mature at the right place and time. But in MS, this normally protective timing mechanism appears to get stuck.
"We were surprised to find that SOX6 can so tightly control when oligodendrocytes mature," said Kevin Allan, the study's co-lead author and recent graduate of the School of Medicine's Medical Scientist Training Program. "This gives us a potential explanation for why these cells often cannot remyelinate damaged neurons in diseases like MS."
When the researchers examined brain tissue data from people with MS, they saw an unusually high number of cells stuck in this SOX6-linked immature state. But this stalled maturation seems to be specific to MS: there was no evidence of it in samples from Alzheimer's and Parkinson's disease patients.
To test whether releasing the brake could accelerate development, the team used a targeted molecular drug called an antisense oligonucleotide (ASO) to reduce SOX6 in mouse models. Within days, the treated cells matured and began to myelinate nearby neurons.
"Our findings suggest that oligodendrocytes in MS are not permanently broken, but may simply be stalled," said Jesse Zhan, the study's co-lead author and medical student in the School of Medicine's Medical Scientist Training Program. "More importantly, we show that it is possible to release the brakes on these cells to resume their vital functions in the brain."
Additional collaborators and contributing researchers include Andrew Morton, Erin Cohn, Marissa Scavuzzo, Anushka Nikhil, Matthew Elitt, Benjamin Clayton, Lucille Hu, Elizabeth Shick, Hannah Olsen, Daniel Factor, Peter Scacheri, and Tyler Miller from Case Western Reserve School of Medicine; Gemma Bachmann and Berit Powers from Ionis Pharmaceuticals; Jonathan Henninger and Richard Young from the Whitehead Institute; and Jost Vrabic and Charles Lin from Baylor College of Medicine.
The study was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute, the New York Stem Cell Foundation and the National Multiple Sclerosis Society. sTF5 Care and the Annadata, Enrile, Geller, Goodman, Long, Peterson, Walter and Weidenthal families contributed philanthropic support.
