Research shows hyaluronic acid (HA) molecule triggers a pathway that is normally used by the immune system to prevent excessive damage but may contribute to chronic white matter injury by completely blocking repair operations. The study, published in the May issue of Journal of Clinical Investigation, was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
"This study uncovers a new player in white matter disease and identifies a potential drug target," said Jim Koenig, Ph.D., program director at NINDS. "It also describes a unique situation in which the brain tries to take over immune system functions, with devastating results." White matter, also known as myelin, is formed by oligodendrocytes, specialized cells that come from developing cells called oligodendrocyte progenitor cells (OPCs). Studies have shown that in cases of chronic white matter injury, OPCs accumulate in the lesions, ready to help, but for some reason are not able to produce myelin. A very large molecule called hyaluronic acid (HA) also accumulates in the lesions and is broken down into small fragments that are thought to prevent OPCs from producing myelin.
A team led by Stephen Back, M.D., Ph.D., professor of pediatrics and neurology at the Oregon Health & Science University in Portland, took a detailed look at the HA fragments to see how they block myelin repair. Using state-of-the-art techniques, Dr. Back and his colleagues were able to create HA fragments of different sizes. Results showed that only one specific size of HA, the 210 kDa fragment, had an effect on OPC proliferation. Dr. Back and his team treated rat cells that mimicked white matter disease with the 210 kDa HA fragment. They discovered that the HA initially turned on molecules associated with myelination but then shut them down completely, a strategy that is similar to immune tolerance, which is used by the immune system to prevent severe tissue injury from an ongoing, damaging response to bacteria and viruses. "We showed that HA creates not just a roadblock to myelin repair after injury, it also shuts down all of the possible detours," said Dr. Back. "Tolerance can be helpful in preventing the brain from repairing itself too quickly, but in some disease conditions, it can turn into a detrimental response."
"For decades HA was thought of as simply a glue holding everything together. In recent years, we have come to learn how critical this molecule is for various pathways and potentially, many neurological disorders," said Dr. Back. More research is needed to learn about the molecules involved in white matter repair as well as the role of different HA fragments in these processes.