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University of Iowa News Release

June 17, 2003

Muscle Protein Has Role In Nerve Disorders

A protein that plays a role in muscular dystrophies also may be involved in peripheral neuropathy -- disorders of the nerves that carry messages between the brain and the rest of the body. The findings, by University of Iowa researchers and colleagues, may shed light on the causes and mechanisms of human peripheral neuropathies, which cause pain, numbness and muscle wasting.

Peripheral neuropathies can be acquired as a result of diseases including diabetes and Hansen's disease (leprosy) or can be inherited. Some congenital peripheral neuropathies (those present at birth) can cause limb deformities. The UI study may suggest new treatment strategies for these conditions.

Kevin Campbell, Ph.D., a Howard Hughes Medical Institute investigator and UI professor and interim head of physiology and biophysics and professor of neurology, led the team investigating the role of the protein, dystroglycan, in the peripheral nervous system. The study appeared in the June 5 issue of Neuron.

In the peripheral nervous system, dystroglycan is found in Schwann cells, which wrap themselves around peripheral axons (nerve fibers) and protect them by producing a myelin sheath. The sheath allows nerve impulses to move faster and more efficiently along the nerves. If nerve fibers are the body's electrical wiring, then the myelin sheath represents the insulation.

Each Schwann cell envelops a short stretch of axon, and the gaps between each section of the myelin sheath are called nodes of Ranvier. Ions flow through sodium channels at these nodes generating action potentials or nerve impulses. This signal is transmitted down the nerve fiber from one node to the next.

The researchers found that dystroglycan is necessary to form normal myelin sheaths. They also discovered that loss of the protein disrupts the structure of the nodes of Ranvier and affects the nerve's ability to transmit nerve impulses. The results suggest that disruption of dystroglycan's functions may play a role in various neuropathic disorders.

The UI team developed mice that lacked dystroglycan in their Schwann cells. This specific mutation caused progressive nerve damage in the mice. The mice were less coordinated than normal mice and their sensitivity to heat and pressure was altered. The team also showed that nerve impulses traveled more slowly in these mice.

The researchers examined the peripheral nerve fibers and saw that the myelin sheaths were abnormally folded, indicating that dystroglycan is important for normal myelination of peripheral nerve. This finding was not unexpected, as several earlier studies had suggested that dystroglycan might be involved in myelination.

However, the myelin sheath abnormalities did not seem severe enough to account for the significant reduction in the speed of nerve impulses in the mutant mice. This puzzle led the researchers to another discovery: the absence of dystroglycan appears to disrupt the normal structure of the nodes of Ranvier that are necessary to rapidly transmit nerve impulses along the nerve. In particular, loss of dystroglycan reduces the density of sodium channels that cluster at each node and are critical for normal transmission of nerve impulses.

"The slowing in the time it takes for a signal to travel along the nerve, is really interesting," Campbell said. "We think that dystroglycan may play a role in organizing the sodium channels at the nodes and setting up the proper nodal structure for efficient transmission of nerve signals.

"We initially identified dystroglycan in the muscular dystrophy field and now it is giving us clues to causes of and possible mechanisms of peripheral neuropathies," Campbell said. "Research is not always predictable; studies in one area can often reveal findings that are important for an entirely different area of science. Hopefully, in addition to insights on peripheral neuropathies, this work will suggest new ways to think about dystroglycan's function in the central nervous system and muscle too."

In muscle, dystroglycan contributes to a protein complex that links the inner cell structures with the cell's surrounding environment. Research over the past decade has shown that many muscular dystrophies are caused by genetic defects in individual protein components, which disrupt the whole complex.

Similarly, in Schwann cells, dystroglycan also appears to be the lynchpin of a protein complex connecting components inside and outside of cells. The UI study showed that loss of dystroglycan disrupts this complex in Schwann cells and leads to neuropathy.

"Our study has clinical implications for diverse hereditary neuropathies and muscular dystrophies," said Steven Moore, M.D., Ph.D., UI professor of pathology and a staff physician at the Veterans Affairs Medical Center in Iowa City. "Gene mutations leading to abnormalities in dystroglycan or closely associated proteins must now be considered as possible causes of inherited peripheral neuropathies. Also, peripheral nerve dysfunction must now be more critically considered a part of the overall clinical picture in patients presenting primarily with signs and symptoms of muscular dystrophy."

Moore and Fumiaki Saito, M.D., who was a postdoctoral researcher in Campbell's lab, were co-first authors of the study. Saito now is a neurologist at Teikyo University School of Medicine, Japan.

In addition to Campbell, Moore and Saito, the UI researchers involved in the study included Rita Barresi, Ph.D.; Michael Henry, Ph.D.; Susan Ross-Barta; Roger Williamson, M.D., professor of obstetrics and gynecology; and Kathleen Sluka, Ph.D., associate professor of physical therapy and rehabilitation sciences. Researchers at the following institutions also were part of the team: the University of Wisconsin-Madison, the Johns Hopkins Children's Hospital and the McKusick-Nathans Institute of Genetic Medicine, the University of Edinburgh, Scotland, the Mayo Clinic, Rochester, Minn. and the San Raffaele Scientific Institute, Milan, Italy.

The research was funded in part by grants from the Muscular Dystrophy Association, the National Institutes of Health and an Italian Telethon grant.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com.

STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

MEDIA CONTACT: Jennifer Brown, 319-335-9917, jennifer-l-brown@uiowa.edu

PHOTOS/GRAPHICS: Photos for this story are available for downloading at http://www.physiology.uiowa.edu/campbell/public/KevinMemberPage.htm
http://www.medicine.uiowa.edu/pathology/path_folder/faculty/moore/moore.html