Molecular fats prevent nerve sheath abnormality
CHAPEL HILL - A study led by scientists at the University of North Carolina at Chapel Hill points to a group of lipids (fats) that are crucial to proper formation of the myelin sheath surrounding nerve fibers.
Although without direct clinical implications for human disease, the new findings help solve a scientific puzzle while adding important new knowledge to the molecular biology of myelin and diseases of myelin loss, particularly multiple sclerosis.
A report of the research appears in the December 13 issue of the Journal of Cell Biology.
Myelin, which is 30% protein and 70% lipid, forms the multi-membrane shield that surrounds nerve axons, hair-like extensions of nerve cells that snake off and make connections with other nerve cells. These myelinated connections form the wiring circuitry of both the central (brain and spinal cord) and peripheral nervous systems.
In his laboratory in the UNC Neuroscience Center, Dr. Brian J. Popko, associate professor of biochemistry, studies myelin on two overlapping levels. "We're interested in the basic molecular biology and biochemistry of myelin formation, maintenance and function - a very basic approach to what myelin is, how it's formed and what it does," he said. "We're also interested in the disease MS, an auto-immune response to the person's own myelin that results in its loss. Specifically, we're interested in the effect of the immune response on the myelin sheath and on the myelinating cell."
Popko noted that the myelin sheath is actually segmental, containing regularly spaced unmyelinated gaps known as nodes of Ranvier. These gaps enable electrical impulses to travel down the axon rapidly by jumping from one unmyelinated region to the next. Thus, for a higher nervous system containing millions of neurons, myelin increases the speed at which electrical impulses travel down axons without having to increase axon size.
"In MS, the myelin sheath is stripped away leaving entire segments unmyelinated, and that creates havoc with the electrical impulse. It does not travel down the axon efficiently or in a coordinated fashion, so you have motor coordination problems and other effects."
The myelinating cells Popko studies are oligodendrocytes, which myelinate the central nervous system. In the early 1990s, he and his colleagues identified the gene that encodes an enzyme (CGT) that's responsible for the synthesis of a particular myelin lipid type - galactolipids. These lipids are substantial components of myelin.
"By identifying this gene, we have been able to take a genetic approach to figure out what these lipids are doing," he said.
Using gene "knockout" technology, Popko's lab generated mouse mutants incapable of producing CGT, thus incapable of producing myelin galactolipids.
"We were surprised to find that even in their absence, myelin still formed," Popko said. "But the animals had a phenotype we would predict for mice with little or no myelin."
Beginning at age two to three weeks - the age at which myelin forms - the mice developed a very severe persistent tremor.
"Although we were not surprised by this phenotype, we were surprised when we initially looked at the myelin and found that it looked relatively normal," said Popko. "And so these animals have severe electrophysiological abnormalities in the face of what appear to be normal myelin." This puzzling situation apparently has been solved. In a series of studies using electron and confocal microscopy to examine very thin cellular layers, Jeffrey L. Dupree, a postdoctoral researcher in Popko's lab and lead-author of the new report found abnormalities in the nodes of Ranvier, the unmyelinated regions of the axon where the sodium channels are located.
"The nodes are much larger, the gaps between myelinated segments are less regular - sometimes bigger and sometimes nonexistent. Sometimes the myelin segments overlap so that you don't get any node at all," Popko explained. In addition, potassium channels were scrambled out of position and the lateral myelin loops that normally adhere tightly to the axon appeared unwound. Moreover, a protein thought to play an important role in myelin adhesion was not concentrated in its usual location.
"In the face of these abnormalities, the electrical impulse will be abnormal down the length of the axon, there will be no coordination of electrical impulses," Popko said.
He adds that the molecular abnormalities associated with the absence of galactolipids may also play a role in myelin loss and its behavioral effects. "When the mutant animals get older, sheaths of myelin fall apart. And they develop paralysis."
Funding for this research comes from the National Institutes of Health.
University of North Carolina School of Medicine. December 1999.
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