Protein Lets Brain Fix Damage from MS, Other Disorders

A protein that helps build the brain in infants and children may aid efforts to restore damage from multiple sclerosis (MS) and other neurodegenerative diseases, researchers at Washington University School of Medicine in St. Louis have found.

In a mouse model of MS, researchers found that the protein, CXCR4, is essential for repairing myelin, a protective sheath that covers nerve cell branches. MS and other disorders damage myelin, and this damage is linked to loss of the branches inside the myelin.

"In MS patients, myelin repair occurs inconsistently for reasons that aren't clear," says senior author Robyn Klein, MD, PhD, associate professor of medicine and of neurobiology. "Understanding the nature of that problem is a priority because when myelin isn't repaired, the chances that an MS flare-up will inflict lasting harm seem to increase."

The findings appear online in The Proceedings of the National Academy of Sciences.

Mouse models typically mimic MS symptoms by causing chronic immune cell infiltration in the brain, but, according to Klein, the ongoing immune damage caused by the cells makes it difficult for researchers to focus on what the brain does to repair myelin.

For the study, Klein and first author and postdoctoral fellow Jigisha Patel, PhD, used a non-inflammatory model that involves giving mice food containing cuprizone, a compound that causes the death of cells that form myelin in the central nervous system. After six weeks, these cells, known as oligodendrocytes, are dead, and the corpus callosum, a structure that connects the left and right hemispheres of the brain, has lost its myelin. If cuprizone is then removed from the mouse diet, new cells migrate to the area that restore the myelin by becoming mature oligodendrocytes.

Klein's investigations began with the processes triggered by dying oligodendrocytes while mice are still on the cuprizone diet. The dying cells activate other support cells in the brain, causing them to express inflammatory factors.

Klein showed that levels of a receptor for an inflammatory factor, CXCR4, peaked at six weeks. If researchers continued feeding the mice cuprizone for 12 weeks, levels of the inflammatory factor and its receptor dropped significantly. At 12 weeks the mice were also unable to restore myelin, suggesting a potential connection between myelin repair and CXCR4.

"This was a surprise, because the main thing CXCR4 has been known for is its role in forming the brain, not healing the brain," Klein says. "But we did know that injury increases the number of brain cells that make CXCR4, so it wasn't an unreasonable place to look."

Klein showed that the cells destined to become oligodendrocytes and repair myelin damage, known as neural precursor cells, have high levels of the CXCR4. The cells come up to the corpus callosum from an area below the ventricles, a noncellular area filled with cerebrospinal fluid.