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Molecular Partners Required For Appropriate Neuronal Gene Repression

Oregon Health & Science University researchers have identified some of the key factors that prevent the repair of brain damage caused by multiple sclerosis (MS), complications of premature birth, and other diseases and conditions. The findings offer important clues about why the nervous system fails to repair itself and suggest ways that at least some forms of brain damage could be reversed. The research is published in the August edition of the scientific journal Nature Medicine.

"For many years, scientists have understood that damage to the insulation-like sheath surrounding nerve cells in the brain, called myelin, is part of the disease process for MS and other brain disorders," said Larry Sherman, Ph.D., an associate scientist in the Division of Neuroscience at the Oregon National Primate Research Center and an adjunct associate professor of cell and developmental biology in the OHSU School of Medicine. "In recent years, it became clear that there were cells at the sites of this damage that should have the capacity to repair the brain and spinal cord but they fail to do so. Our studies have revealed that there is a particular signal in the damaged brain that prevents these cells from restoring lost myelin. We're hopeful that we can develop methods to counteract this process in animal models in our search for human treatments."

Other key OHSU researchers involved in the study are: Stephen Back, M.D., Ph.D., an associate professor of pediatrics and neurology in the OHSU School of Medicine; and Bruce Bebo Jr., Ph.D., a scientist in the OHSU Neurological Sciences Institute and an associate professor of neurology in the OHSU School of Medicine.

The researchers decided to collaborate following a key finding in Sherman's lab where scientists were studying a mouse model for tumors in the central nervous system. The mice had been bred to overproduce a protein which had been implicated previously in tumor formation. The protein, called CD44, is frequently found in limited amounts in the brains of both healthy mice and humans. However, instead of developing tumors, the mice with elevated CD44 developed tremors similar to those seen in individuals with multiple sclerosis (MS).

Further investigation revealed that the tremors were associated with the loss of myelin sheaths on nerve cells, very similar to the myelin loss associated with MS and other neurological diseases, as well as in premature infants. In addition, Sherman's lab found large amounts of hyaluronic acid (HA), a carbohydrate, in the brains of these mice. A comparison to brain tissue of deceased human MS patients also revealed heightened levels of HA, apparently caused by the increased presence of CD44 -- something which had never been noted before. It was at this point that Sherman contacted Bebo, who had been studying an MS-like disease in mice for many years, and they began a collaboration to study how HA accumulated in regions of the nervous system where myelin had been destroyed.

"These investigations revealed that oligodendrocytes, which are cells that form myelin in the brain, were prevented from repairing the damaged myelin when there were elevated levels of HA," explained Bebo. "By studying another mouse model in my lab, we made the connection between heightened levels of HA -- specifically a high-molecular weight version of HA -- and myelin loss in an MS-like disease in mice. We also identified the cells that were making the HA and determined that HA accumulation was linked to an overabundance of the CD44 protein."

To further understand the process, Bebo and Sherman joined forces with Back, a pediatric neurologist and researcher studying developmental brain injury in premature infants. Previous research by Back and other scientists had revealed a link between the white matter brain damage associated with premature birth and damage to immature cells in the brain and spinal cord, called oligodendrocyte progenitors. These precursor cells give rise to all of the mature oligodendrocytes that make myelin throughout life.

Back's lab provided the team with tissue cultures of immature rat oligodendrocytes. The researchers then applied HA to these cells which indeed kept the immature cells from maturing into myelin-producing cells. In another key experiment, Sherman and Back confirmed in another animal model of MS that injection of the HA into damaged myelin prevented myelin from reforming where it had already been destroyed. Conversely, they showed that reducing HA levels or making the HA inactive allows myelin to once again form.

"It is our hope that we can interfere with this disease process at one or multiple stages," explained Back. "Of course for those already battling a myelin-destroying disease, you would want to try and promote the return of myelin-forming cells. This general area of research is of particular interest to me in my attempts to counteract the white matter brain damage that is often associated with premature birth and can lead to a form of cerebral palsy (CP). Our early findings have shown that scar tissue in the brains of premature infants who die during intensive care also produces HA. We believe the HA may also prevent the production of myelin-producing cells and be related to the motor impairment seen in CP. My hope is that this work will benefit a wide range of patients from premature infants to stroke victims to those suffering from debilitating neurological diseases such as MS where repair of damaged myelin does not occur."

Sherman shares this hope. "This discovery has revealed a target for therapies and opens the door to the exciting possibility that we may, one day, be able to not only stop disease progression but also repair damage that is already there. The future efforts of our three labs will be aimed at exactly that goal. "

"The work of these investigators offers new hope to people with MS and their families," said Na tional MS Society Oregon Chapter President Graham McReynolds. "Treatments and nerve repair research that once seemed decades away may now be within our grasp. This is a time of great promise for MS research."

"Preterm birth can interrupt the normal myelination process. Therefore, this report may help to explain the brain damage seen in premature infants, some of whom develop cerebral palsy," said Michael Katz, M.D., senior vice president for research and global programs at the March of Dimes, which supported Dr. Back's research. "More than 470,000 babies are born prematurely each year. Until we find the answers to preventing prematurity, research such as this may lead us to new ways to prevent brain damage and has the potential to improve the lives of thousands of infants. "

Additional collaborative research took place in the laboratory of Mahendra Rao at the National Institute on Aging, a component of the National Institutes of Health; and in the laboratory of Bruce Trapp at the Lerner Research Institute at The Cleveland Clinic.



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