Diseases like multiple sclerosis are characterized by a loss of myelin, the fatty sheath that insulates many nerve fibers. Demyelination of neurons makes them work more slowly - and eventually can cause them to die.
Now researchers in the neurology department at the School of Medicine have discovered a protein that can help prevent damage to demyelinated neurons - and surprisingly, the protein is made in the myelin itself.
The protein, myelin-associated glycoprotein (MAG), is found in virtually all myelin. As its name suggests, it consists of complex sugars bound to protein. The team, led by John Griffin, showed that MAG can help cells resist damage and degeneration, both in cell culture and in animal models.
Specifically, MAG helps protect the axon, the long protrusion from a neuron that carries the neural signal. It is the axon that is wrapped in myelin, so the axon is most susceptible to damage after demyelination.
MAG is known to act as a signaling molecule between axons and the surrounding myelin and has even been shown to have a role in regulating the diameter of axons.
Griffin's group began their work by examining MAG knock-out mice, that is, mice that were genetically engineered not to have any MAG protein. In these mice, there was a constantly low level of axonal degeneration, involving about one in every 200 neurons.
The researchers hypothesized that MAG's presence should also help decrease a neuron's vulnerability to outside insults, such as chemical toxins. Experiments demonstrated that MAG knock-out mice were much more vulnerable to acrylamide, a toxin known to cause axonal degeneration, than were normal mice. These mice had severe motor impairments and had difficulty with simple motor tasks.
The most important experiments linked MAG's activity to multiple sclerosis (MS). A mouse model of MS, called experimental autoimmune encephalomyelitis, was used to demonstrate MAG's important role in decreasing the vulnerability of axons to inflammation.
Four weeks after the model disease was induced, mice without MAG had a loss of axons that was more than 50 percent greater than the normal mice.
There is some hope that MAG might be useful as a clinical treatment. When the protein was suspended in liquid and administered to cells in culture or to live animals, axonal degeneration was largely prevented.
Cells treated with soluble MAG were also more resistant to the toxic effects of vincristine, a chemotherapeutic agent that is ordinarily quite dangerous for neurons.
The researchers hypothesize that MAG's protective effects are due to its ability to stabilize microtubules, part of the internal "skeleton" of neurons and other cells. This cytoskeleton is responsible for preserving the cell's structural integrity, and it also plays a role in the response to injury.
Understanding the role of MAG in maintaining axonal health opens a new door to the treatment of MS and other diseases.
By exploiting the abilities of this naturally occurring protein, researchers may be able to develop successful therapies for an entire group of devastating disorders.
