A novel study has identified a molecule that may be critical to the repair of white matter. The new findings suggest that the molecule triggers a pathway that is normally used by the immune system to prevent excessive damage but may actually contribute to chronic white matter injury by completely blocking repair operations.
“This study uncovers a new player in white matter disease and identifies a potential drug target,” commented Jim Koenig, the Program Director at the National Institute of Neurological Disorders and Stroke (MD, USA). “It also describes a unique situation in which the brain tries to take over immune system functions, with devastating results.”
Studies have demonstrated that in cases of chronic white matter injury, oligodendrocyte progenitor cells (OPCs) accumulate in the lesions, ready to assist, however, are not able to produce myelin for unknown reasons. A large molecule termed hyaluronic acid (HA) also accumulates in these lesions and is broken down into small fragments that are thought to prevent OPCs from producing myelin.
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In the study, which was recently published in The Journal of Clinical Investigation, researchers examined HA fragments of varying sizes to further observe how they block myelin repair.
Results from the investigation revealed that only one specific size of HA – the 210 kDa fragment – had an effect on OPC proliferation.
The researchers then treated rat cells that mimicked white matter disease with the 210 kDa HA fragment and discovered that HA initially turned on molecules associated with myelination but then shut them down completely – a strategy that is similar to immune tolerance.
“We showed that HA creates not just a roadblock to myelin repair after injury, it also shuts down all of the possible detours,” explained Stephen Back (Oregon Health & Science University, OR, USA), lead author of the study. “Tolerance can be helpful in preventing the brain from repairing itself too quickly, but in some conditions, it can turn into a detrimental response.”
Additionally, the scientists also discovered that the 210 kDa fragment signals to the TLR4 protein to activate FoxO3, which helps control the activity of genes involved in myelin repair. This activation of FoxO3 eventually leads to a decrease in the activity of myelin-related genes and a slowdown in white matter repair. However, this process only takes place if HA is present.
When looking at human brain tissues affected by white matter injury and multiple sclerosis, the researchers discovered activated FoxO3 in OPCs that were blocked from producing myelin.
“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,” concluded Back.
More research is required to understand the molecules involved in white matter repair as well as the role of different HA fragments in these processes.
Sources: Srivastava T, Diba P, Dean JM et al. A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. J. Clin. Invest. doi:10.1172/JCI94158 (2018) (Epub ahead of print); www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/Scientists-discover-roadblocks-stop-brain-white