Diseases of the covering of nerve cells -- called the myelin sheath -- can be quite debilitating and affect hundreds of thousands of people each year. Multiple sclerosis, which afflicts nerve cells in the brain, is one of the most well known. As part of a long-term investigation, researchers at the University of Pennsylvania Medical Center have demonstrated for the first time how a biochemical channel important for the exchange of cell nutrients links the multiple layers of myelin to the outside space.
"This is a big breakthrough for understanding how myelin works, with implications for all demyelinating diseases, including multiple sclerosis," says Steven Scherer, MD, PhD, associate professor of neurology, who collaborated with Rita Balice-Gordon, PhD, assistant professor of neuroscience, and former Penn combined degree student Linda J. Bone, MD, PhD, on this study.
In earlier work, mutations in components of the channel were associated with inherited forms of neuropathies. Specifically, five years ago, former Penn neurologist Kenneth H. Fischbeck, MD, and Scherer reported that mutations in connexin32 -- a protein found in myelin-producing as well as other cells -- cause X-linked Charcot-Marie-Tooth disease (CMTX), a genetic disorder that produces progressive degeneration of peripheral nerves. One out of 3,000 people suffer from Charcot-Marie-Tooth disease, with 10 to 20 percent of those having this particular inherited form. This led the research team to reappraise the function of connexin32 in myelinating cells. They hypothesized that connexin32 forms part of a six-sided channel wall -- called the gap junction -- that couples the multiple layers of the sheath to the outside, extracellular space. "Our most recent work directly demonstrates the channel's function in the myelin sheath for the first time," says Scherer. The researchers report their findings in the August 24 issue of the Journal of Cell Biology.
The myelin sheath is a unique cellular adaptation found in most vertebrates. "It's very peculiar in that it's like a sleeping bag all rolled up around the axon, the nerve cell inside," remarks Scherer. The sheath allows for the fast conduction times seen in higher vertebrates. Because of its many layers, the sheath might limit diffusion of necessary substances to and from the cell. "But nature has circumvented that problem with gap junctions," he explains.
"These channels provide a radial path for ions and small molecules that we believe is a thousand times shorter and a million times faster than traveling the entire circumference of the sheath," says Balice-Gordon. "We used intracellular dye injections in cultures of myelinating cells and video microscopy to directly demonstrate that this short-cut exists."
In labs all over the world, about 160 mutations have been discovered for connexin32. One group of mutated proteins can still form functional gap junctions, but it remains to be seen how these result in inherited neuropathies. In general, though, as the myelinating cells break down due to these mutations, they impart pathological changes onto the axon. "The mechanism of that might be related to potassium ion movement through the gap junctions, but this is just a hypothesis right now," states Scherer.
"Certainly in the narrowest sense this research ought to lead to some treatments for CMTX," adds Scherer. "We ought to be able to someday design therapies based on our growing knowledge of how the mutations affect the sheath and the passage of ions through gap junctions." So far, the team has been able to express in transgenic mice both normal and mutant connexin32 genes in myelinating cells. This work indicates that these mutations have altered the function of the cells and could account for the demyelinating neuropathies seen in the transgenic mice.
This research was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association.
Editor's Note: Dr. Scherer can be reached at (215) 573-3198 or scherer@mail.med.upenn.edu.
The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website (http://www.med.upenn.edu); EurekAlert! (http://www.eurekalert.org), a resource sponsored by the American Association for the Advancement of Science; and Newswise (http://www.newswise.com).
Journal
Journal of Cell Biology