Search the Health Library
Get the facts on diseases, conditions, tests and procedures.
I Want To...
I Want To...
Find Research Faculty
Enter the last name, specialty or keyword for your search below.
School of Medicine
I Want to...
Share this page: More
For Motor Neurons: Mother May I?
September 2006--For all the medical advancements since ancient times, functional recovery following spinal cord injury remains as elusive now as when the Roman physician Galen in the second century first described the central nervous system (CNS) and the effects of nerve damage.
What makes that especially maddening isn’t the fact that nerve cells never grow back—as successful reattachments of fingers or even hands demonstrate—but that in the brain and spinal cord, they’re prevented from doing so by molecular “stop signs” known as axon regeneration inhibitors (ARIs).
“If we could block these inhibitors pharmacologically,” says neuroscientist Ronald Schnaar, “we could restore axon regeneration in the CNS, if only partly.”
Schnaar first stumbled upon ARIs a decade ago. He was studying intercellular interactions, especially the role of gangliosides, the glycolipids that dominate a nerve cell’s surface. Given the task of identifying certain ganglioside binding partners, his graduate student, Lynda Yang, spotted myelin-associated glycoprotein (MAG) in one of her screens.
MAG-ganglioside binding, it turned out, is critical for keeping a nerve cell’s myelin insulation together: Nerves in mice engineered to lack proper gangliosides degenerate in a way similar to multiple sclerosis. While that’s interesting in its own right, the real intrigue for Schnaar was in two journal articles suggesting that MAG might also inhibit axon regrowth.
“So I reasoned, if MAG’s handshake with both an axon’s myelin and its surface gangliosides is important to keep myelin stabile,” he says, “it might also be important in this other role—inhibiting axon growth after injury.”
Schnaar tested axon growth under telling conditions. One experiment looked at nerve cells from animals with no gangliosides. Another added a soluble sugar to compete for MAG binding. A third cut gangliosides with the enzyme sialidase. Schnaar found that all these disruptions could restore axon regeneration in vitro.
Ready to test his finds on animal models, Schnaar saw the story take an interesting twist.
Re-enter Lynda Yang. After graduating from Hopkins with an M.D./Ph.D., she began a residency at the University of Michigan, where she developed an interest in a CNS injury known as a brachial plexus avulsion. This injury occurs when a violent force jerks one arm away from the rest of the body, ripping nerve endings from the spinal cord. Without a connection, the affected arm hangs limp, its dead weight straining the body. Amputating the limb is typical.
Yang, however, had spent a summer in England becoming familiar with an experimental technique of grafting an expendable peripheral nerve between the spinal cord and injured arm. The hope is that the graft will connect to the CNS as a bridge. While this approach sometimes restores nerve function, low success rate and complications haven’t warranted practical use.
Completing her residency, Yang went on a one-year research sabbatical—the perfect opportunity for a Hopkins reunion.
“Ron had really advanced the MAG project,” she says, “and I thought it would be great to combine my new surgical knowledge with his biochemical skills.”
Their goal was to optimize a rat model of brachial plexus injury and see if MAG inhibition could restore regeneration.
“If we could improve efficiency,” says Yang, “it could help tip the risk/reward balance for this experimental therapy.”
Along with Schnaar and biomedical engineer Larry Schramm, an expert on spinal cord axons, Yang surgically engineered nerve damage in rats and then tested the effects of sialidase—the approach with the most robust in vitro effect. Sialidase treatment extended three times more spinal axons to the graft.
“In fact, it was about the same number of axons as normally leave that segment of the spinal cord,” says Schnaar.
Back at Michigan, Yang continued to fine-tune her brachial plexus model to understand more of MAG’s underlying mechanisms. With treating patients as her ultimate goal, she has also opened a pediatric clinic for brachial plexus injuries. Childbirth trauma is a leading cause.
Schnaar and Schramm turned to a more complicated animal model of CNS injury, spinal contusion. In a contusion, the backbone shifts directly into the spinal cord, causing axons to pinch off and reseal. While their distal ends slowly degenerate, the axon fragment still attached to the spinal nerve cell remains healthy, if dormant.
“Our hope is to induce those axons to re-grow, to get function back,” Schnaar notes. “All of us are very enthusiastic about these studies.”
Improving Recovery from Spinal Cord Injury