Blocking the production of a protein called FoxO3 can boost brain repair after injury, a finding that could lead to new treatments for cerebral palsy, multiple sclerosis, and dementia, a study suggests.
The study, “A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors,” appeared in the Journal of Clinical Investigation.
Hyaluronic acid is a naturally occurring type of sugar, one of the largest molecules in the human body. It is one of the main components of the extracellular matrix, the framework providing structural and biochemical support to cells.
This molecule accumulates in areas of damage within the brain’s white matter, preventing the repair process upon the loss of the protective layer of nerve fibers called myelin, which can lead to significant impairment in brain function.
Oregon Health & Science University (OHSU) researchers demonstrated that although brain lesions break down hyaluronic acid into a wide range of fragments, only one specific-sized fragment — bHAf — blocks the maturation of brain cells required for brain repair.
This effect was mediated by activating a protein called FoxO3, which suppressed crucial genes in the repair process, called remyelination. Importantly, researchers observed that this blockade prevented the action of other repair signals.
“We’ve identified a molecule that plays the role of the ‘bad actor.’ In essence, it hijacked the molecular machinery of the immune system and repurposed it to shut down brain repair after injury,” Stephen Back, MD, PhD, the study’s senior author, said in a press release. Back is the Clyde and Elda Munson Professor of Pediatric Research and Pediatrics at the OHSU School of Medicine.
“And, while this new molecule may not be easily detected in the brain, FoxO3 may serve as a viable biomarker for identifying its detrimental effects in the white matter, creating an opportunity for further research and targeted therapies to fully reverse the impacts of brain injury for people of all ages,” he said.
These findings provide a novel pathway to find treatments for the physical disabilities associated with white matter injury.
“This discovery means that we now have the potential to start looking at multiple ways of intervening to promote brain repair that weren’t available to use before,” said Larry Sherman, PhD, a professor of cell, developmental and cancer biology at OHSU and one of the study’s co-authors. “By preventing the production of this molecule, we can create an effective pathway to allow the brain to continue its regenerative process. This may help to limit long-term physical and mental disability associated with devastating neurological conditions.”
According to researchers, defining the mechanisms that regulate the generation and actions of bHAf may suggest repair strategies in several neonatal and adult human disorders, including cerebral palsy.
A potential strategy consists of developing molecules that could prevent the generation of hyaluronic acid fragments. Further research of brain repair pathways may also contribute to new therapies such as stem cell transplants, Back said.