OHSU Finding May Offer Hope For Victims Of Multiple Sclerosis

By Joel M. Dahms

What happens when the lines of communication between the brain and the body become unreliable? Like a bad cell phone connection, sometimes the signal doesn't get through. This is what happens in Multiple Sclerosis (MS), a debilitating central nervous system (CNS) disease that causes symptoms such as numbness, extreme fatigue, and paralysis. For most of the nearly 500,000 MS victims nationwide, their symptoms tend to get worse with time and there is no cure.

For unknown reasons, MS is far more common in Northwest natives than in people from other parts of the U.S. So it seems fitting that recent research conducted at Oregon Health & Science University (OHSU) in Portland may lead to new strategies for reversing the damage wrought by MS.

In September's issue of Nature Medicine, a team of OHSU researchers reported identifying an important factor that prevents the brain and spinal cord from repairing the damage done by MS. Most available treatments for MS only manage disease symptoms, so the prospect of reversing the damage is exciting. However, at present the new findings are too preliminary to know if they will translate into effective treatments for the disease.

The culprit is a molecule called hyaluronic acid (HA), which is found throughout the body and functions by holding cells together. OHSU scientists found that HA is more abundant around cells in the brains of both mice and people with diseases like MS that destroy myelin, the fatty covering that surrounds nerves and helps them transmit information. MS occurs because the CNS can't efficiently repair damage done to myelin (called demyelination). Without it, communication between the brain and body often fails.

Lead author on the study was Larry Sherman of OHSU's Oregon National Primate Research Center. He noticed that some mice he had bred to produce extra CD44, a protein found on the cell surface, had unexpected damage to their myelin. He then discovered that HA, which binds to CD44, was highly concentrated around brain cells at sites of myelin damage in these mice, and also in mice with another MS-like disease.

"Next, we went and looked at the brains of deceased MS patients and sure enough, in every single patient we looked at we saw the same thing: tremendous amounts of HA wherever there was demyelination," Sherman says. "We thought, maybe the HA is somehow preventing remyelination." Sherman also found high levels of CD44 in areas of myelin damage in the MS brains. "We think CD44 is sort of acting like a sink that's allowing the HA to accumulate around these cells," Sherman says.

Sherman's lab then joined forces with Stephen Back of OHSU who studies the cells called oligodendrocytes that actually form the myelin in the CNS. Back and Sherman found that when oligodendrocyte precursor cells were grown in a Petri dish in the presence of HA, they failed to mature normally into myelin-producing oligodendrocytes. "These cells were basically in suspended animation," says Back, "but when the HA was washed out, the cells would go on to form normal oligodendrocytes. So it was a reversible effect, which was very exciting."

Sherman, Back, and colleagues surmised that high levels of HA may prevent oligodendrocyte precursor cells (OPCs) from maturing and replacing lost myelin. Perhaps the most convincing evidence for such a mechanism came when the scientists injected normal mice with a chemical that destroys myelin. When the chemical was given alone, the brains of these mice grew new myelin to repair the damage, but when HA was injected along with the demyelinating chemical, this remyelination process failed.

"These findings are exciting to individuals affected by MS because a further understanding of how HA inhibits remyelination may offer the potential for clinical treatments," says Jodie Haselkorn, director of the Veteran's Affairs MS Centers of Excellence West, based in Seattle and Portland.

Currently, the OHSU team is trying to develop such treatment strategies to reverse the myelin damage done in MS, which may also help victims of spinal cord injury and cerebral palsy that also involve myelin damage. One of these strategies is a treatment that breaks down HA specifically at the sites of myelin damage. Another seeks to coax oligodendrocyte precursor cells into ignoring the high levels of HA present.

Both strategies could allow OPCs to mature into adult oligodendrocytes capable of replacing myelin lost to disease. For MS patients, this would restore the lines of communication between the brain and the body and with it, restore hope for a more normal life.

Joel Dahms has an M.S. in neurobiology and is currently studying science writing at the University of Washington.