Molecular "Stop Signs" May Hold Secret Of Nerve Regeneration

"Four thousand years ago, physicians wrote that spinal cord injury was untreatable, and unfortunately it's much the same today," says Ronald L. Schnaar, Ph.D., professor of pharmacology and of neuroscience at Hopkins. "But the basic-science framework for improving this situation is quickly emerging."

In adult mammals, including humans, molecular signals carefully control the number of contacts nerve cells make by inhibiting new connections. When the brain or spinal cord has been damaged, the goal is to neutralize those inhibitors so that the long tentacles of nerve cells, the axons, might reestablish their broken connections, says Schnaar.

The research team reports identifying brain chemicals that are involved in the ability of one of the inhibitors to prevent injured nerve cells from connecting to other nerves or muscles. By keeping the chemicals from interacting with the inhibitor, the researchers were able to stimulate damaged nerve cells to regenerate in laboratory dishes. Their report is in the June 11 issue of the Proceedings of the National Academy of Sciences.

"In the central nervous system, once an axon is interrupted in some way, through disease or injury, generally it's stopped dead in its tracks, but in the rest of the body, damaged axons can re-grow," says Schnaar. "To make headway in treating brain and spinal cord injury, we need to attack this problem from a number of angles, and our studies have provided an additional target for intervention."

Of the "stop signs" identified so far, Schnaar's team focused on MAG, or myelin-associated glycoprotein, which is part of the myelin wrapping that insulates all nerve cells. Understanding how the newly identified molecules responsible for MAG's inhibitory effect -- called gangliosides -- interact with MAG to send the "stop" signal to the nerve may lead one day to potential treatments, say the scientists.

In their experiments with rat and mouse cells, Hopkins postdoctoral researcher Alka Vyas tested four ways of stopping MAG and the gangliosides from interacting: destroying part of the ganglioside where MAG usually attaches, limiting the amount of the gangliosides made by the cells, using antibodies to block MAG or using antibodies to block the gangliosides. The research team now is focused on determining exactly how the gangliosides and MAG work together to stop nerve regeneration.

The work was funded by the National Institutes of Health, the National Multiple Sclerosis Society and the Stollof Family Fund. Other authors on the report are Himatkumar Patel, Susan Fromholt, Marija Heffer-Lauc, Kavita Vyas and Jiyoung Dang of Johns Hopkins; and Melitta Schachner of the University of Hamburg, Germany.