PORTLAND, Ore. -- Oregon Health & Science University researchershave identified some of the key factors that prevent the repair ofbrain damage caused by multiple sclerosis (MS), complications ofpremature birth, and other diseases and conditions. The findings offerimportant clues about why the nervous system fails to repair itself andsuggest ways that at least some forms of brain damage could bereversed. The research is published in the August edition of thescientific journal Nature Medicine.
"For many years, scientists have understood that damage to theinsulation-like sheath surrounding nerve cells in the brain, calledmyelin, is part of the disease process for MS and other braindisorders," said Larry Sherman, Ph.D., an associate scientist in theDivision of Neuroscience at the Oregon National Primate Research Centerand an adjunct associate professor of cell and developmental biology inthe OHSU School of Medicine. "In recent years, it became clear thatthere were cells at the sites of this damage that should have thecapacity to repair the brain and spinal cord but they fail to do so.Our studies have revealed that there is a particular signal in thedamaged brain that prevents these cells from restoring lost myelin.We're hopeful that we can develop methods to counteract this process inanimal models in our search for human treatments."
Other key OHSU researchers involved in the study are: StephenBack, M.D., Ph.D., an associate professor of pediatrics and neurologyin the OHSU School of Medicine; and Bruce Bebo Jr., Ph.D., a scientistin the OHSU Neurological Sciences Institute and an associate professorof neurology in the OHSU School of Medicine.
The researchers decided to collaborate following a key findingin Sherman's lab where scientists were studying a mouse model fortumors in the central nervous system. The mice had been bred tooverproduce a protein which had been implicated previously in tumorformation. The protein, called CD44, is frequently found in limitedamounts in the brains of both healthy mice and humans. However, insteadof developing tumors, the mice with elevated CD44 developed tremorssimilar to those seen in individuals with multiple sclerosis (MS).
Further investigation revealed that the tremors wereassociated with the loss of myelin sheaths on nerve cells, very similarto the myelin loss associated with MS and other neurological diseases,as well as in premature infants. In addition, Sherman's lab found largeamounts of hyaluronic acid (HA), a carbohydrate, in the brains of thesemice. A comparison to brain tissue of deceased human MS patients alsorevealed heightened levels of HA, apparently caused by the increasedpresence of CD44 -- something which had never been noted before. It wasat this point that Sherman contacted Bebo, who had been studying anMS-like disease in mice for many years, and they began a collaborationto study how HA accumulated in regions of the nervous system wheremyelin had been destroyed.
"These investigations revealed that oligodendrocytes, whichare cells that form myelin in the brain, were prevented from repairingthe damaged myelin when there were elevated levels of HA," explainedBebo. "By studying another mouse model in my lab, we made theconnection between heightened levels of HA -- specifically ahigh-molecular weight version of HA -- and myelin loss in an MS-likedisease in mice. We also identified the cells that were making the HAand determined that HA accumulation was linked to an overabundance ofthe CD44 protein."
To further understand the process, Bebo and Sherman joinedforces with Back, a pediatric neurologist and researcher studyingdevelopmental brain injury in premature infants. Previous research byBack and other scientists had revealed a link between the white matterbrain damage associated with premature birth and damage to immaturecells in the brain and spinal cord, called oligodendrocyte progenitors.These precursor cells give rise to all of the mature oligodendrocytesthat make myelin throughout life.
Back's lab provided the team with tissue cultures of immaturerat oligodendrocytes. The researchers then applied HA to these cellswhich indeed kept the immature cells from maturing intomyelin-producing cells. In another key experiment, Sherman and Backconfirmed in another animal model of MS that injection of the HA intodamaged myelin prevented myelin from reforming where it had alreadybeen destroyed. Conversely, they showed that reducing HA levels ormaking the HA inactive allows myelin to once again form.
"It is our hope that we can interfere with this diseaseprocess at one or multiple stages," explained Back. "Of course forthose already battling a myelin-destroying disease, you would want totry and promote the return of myelin-forming cells. This general areaof research is of particular interest to me in my attempts tocounteract the white matter brain damage that is often associated withpremature birth and can lead to a form of cerebral palsy (CP). Ourearly findings have shown that scar tissue in the brains of prematureinfants who die during intensive care also produces HA. We believe theHA may also prevent the production of myelin-producing cells and berelated to the motor impairment seen in CP. My hope is that this workwill benefit a wide range of patients from premature infants to strokevictims to those suffering from debilitating neurological diseases suchas MS where repair of damaged myelin does not occur."
Sherman shares this hope. "This discovery has revealed atarget for therapies and opens the door to the exciting possibilitythat we may, one day, be able to not only stop disease progression butalso repair damage that is already there. The future efforts of ourthree labs will be aimed at exactly that goal. "
"The work of these investigators offers new hope to peoplewith MS and their families," said National MS Society Oregon ChapterPresident Graham McReynolds. "Treatments and nerve repair research thatonce seemed decades away may now be within our grasp. This is a time ofgreat promise for MS research."
"Preterm birth can interrupt the normal myelination process.Therefore, this report may help to explain the brain damage seen inpremature infants, some of whom develop cerebral palsy," said MichaelKatz, M.D., senior vice president for research and global programs atthe March of Dimes, which supported Dr. Back's research. "More than470,000 babies are born prematurely each year. Until we find theanswers to preventing prematurity, research such as this may lead us tonew ways to prevent brain damage and has the potential to improve thelives of thousands of infants. "
Additional collaborative research took place in the laboratoryof Mahendra Rao at the National Institute on Aging, a component of theNational Institutes of Health; and in the laboratory of Bruce Trapp atthe Lerner Research Institute at The Cleveland Clinic.
Funding for this research wasprovided by the National Multiple Sclerosis Society; the March of DimesBirth Defects Foundation; and the National Institute of NeurologicalDisorders and Stroke and the National Institute of Environmental HealthSciences, both of which are branches of the National Institutes ofHealth.
OHSU includes the schools of dentistry, medicine, nursing and scienceand engineering; OHSU Hospital and Doernbecher Children's Hospital;numerous primary care and specialty clinics; multiple researchinstitutes; and several outreach and community service units.
The ONPRC is a registered research institution, inspectedregularly by the United States Department of Agriculture. It operatesin compliance with the Animal Welfare Act and has an assurance ofregulatory compliance on file with the National Institutes of Health.The ONPRC also participates in the voluntary accreditation programoverseen by the Association for Assessment and Accreditation ofLaboratory Animal Care International (AAALAC).
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