October 2001

From University of North Carolina at Chapel Hill

Experiments offer major clue to repairing diseased nerves

CHAPEL HILL -- Using specially designed and bred laboratory mice, scientists at the University of North Carolina at Chapel Hill have discovered that a well-known protein in the body called tumor necrosis factor-alpha plays a central role in how nerves and the brain repair themselves.

The discovery is a surprise, the UNC School of Medicine researchers say, because the protein, a cytokine produced during inflammation, has traditionally been considered something that makes illnesses worse, not better. Taking advantage of the new knowledge potentially could lead to more effective treatments for such illnesses as multiple sclerosis.

"Weíre far from using this in any way to help patients directly, and we donít want to get hopes up prematurely," said Dr. Jenny P.-Y. Ting, Alumni Distinguished professor of microbiology and immunology at the Lineberger Comprehensive Cancer Center and the neurobiology curriculum. "Still, this is a different way of thinking about remyelination that undoubtedly will be useful and important in the future."

Remyelination is the repair process in the brain by which nerve cells regain the natural fatty sheath, called myelin, that surrounds them and allows them to transmit nerve impulses, Ting said. It often occurs to varying degrees in people with multiple sclerosis and other brain illnesses who have suffered demylination. That disease process involves the loss of fat covering nerves -- something like rubber insulation eroded away from electric wires.

A report on the findings will appear in the November issue of Nature Neuroscience and was posted online Oct. 15. Besides Ting, authors include doctoral student and first author Heather A. Arnett, Dr. Glenn K. Matsushima, assistant professor of microbiology and immunology, and Dr. Kinuko Suzuki, professor of pathology and laboratory medicine, all of UNCís Neuroscience Center.

In their experiments, the team relied on an existing mouse model of demyelination that Matsushima has been working on and improving for several years. Employing a technique pioneered by UNCís Dr. Oliver Smithies, researchers at Memorial Sloan-Kettering Cancer Center "knocked out," or disabled, a gene responsible for producing tumor necrosis factor alpha and then bred successive generations of the rodents with that gene not working.

The UNC scientists treated those mice and others whose genes were functional with a toxin called cuprizone that slowly stripped away the myelin coating on nerves in their brains and then observed myelin regeneration indicative of nerve repair. Normal mice recovered completely, but those lacking the functioning tumor necrosis factor-alpha gene did not, which indicated how critical the protein was to the repair process.

"Weíve found that these tumor necrosis factor molecules are very important for the white matter in the brain to repair itself," Ting said. "White matter is part of the brain that allows motor skills, and if you donít have it, you canít move."

"We further found that the repair process acts through a particular pathway that appears to induce the production of nerve precursor cells," Arnett added. "Those cells will eventually differentiate into oligodendrocytes -- cells that make myelin and surround nerve axons."

Tumor necrosis factor is the subject of intense study by medical scientists because it plays so many roles in the body depending on where, when and how much is released, Ting said. Often tied to inflammation, it is believed to stop cell growth, promote cell death and stimulate cell development, among other actions.

Recent clinical trials of several drugs designed to block the alpha form of TNF, which was considered to be a problem, actually made patientsí conditions worse, Arnett said. In part, the UNC experiments were designed to find out why.

"Remyelination does occur to a limited extent in multiple sclerosis patients, but it is never complete,Ē Arnett said. ďIf we could figure out what factors contribute to remyelination, then we could use that information in drugs or other therapies to help patients."

The National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke and the supported the research. Dr. Mike Marino of Memorial Sloan-Kettering Cancer Center in New York collaborated with the UNC scientists.

Note: Ting and Arnett can be reached at 919-966-5538 and 966-2662, respectively. Contact: David Williamson, 919-962-8596

By DAVID WILLIAMSON
UNC News Services












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