When nerves are damaged by the immune system, they lose some of their myelin, a protective coating that is, for unknown reasons, hard to restore. Myelin repair, a new study indicates, is controlled by an epigenetic mechanism that may be subject to therapeutic control. Potential drugs have even been identified. With further development, these drugs could help people who suffer nerve damage caused by autoimmune disease.
The new findings were uncovered by scientists based at Cincinnati Children's Hospital Medical Center. The scientists, led by Q. Richard Lu, Ph.D., presented the details of their work February 12 in the journal Nature Medicine, in an article entitled, “A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration.”
Essentially, the scientists described how they determined that histone deacetylase 3 (HDAC3), an epigenetic enzyme, inhibits the generation of new myelin. They also reported that they inhibited this inhibitor in a mouse model of peripheral nerve injury, an intervention that enhanced myelin growth and regeneration and improved functional recovery.
“HDAC3 antagonizes the myelinogenic neuregulin–PI3K–AKT signaling axis,” the authors of the Nature Medicine article wrote. “Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth.”
To identify possible therapies, the international team of investigators performed small-molecule epigenetic screening for compounds that inhibit enzymes involved in epigenetic changes on chromosomes. “Remarkably, temporary inhibition of HDAC3 robustly accelerated the formation of myelin that helps insulate peripheral nerves,” Dr. Lu said. “This promoted functional recovery in the animals after peripheral nerve injury.”
After peripheral nerve injury, HDAC3 initiates epigenetic changes to chromosomes and gene regulation that excessively restrict myelin regeneration. This results in nerve insulation that is too thin or not totally formed, blocking or slowing signals between the spinal cord, extremities, and organs.
Researchers carefully timed their targeted treatments when inhibiting HDAC3, treating the mouse models of nerve injury only during a critical phase of nerve regeneration. This resulted in the right amount of re-myelination to restore normal function in the animals.
Additional findings suggested that getting the timing right on transient treatment is critical. “Schwann cell–specific deletion of either HDAC3 or TEAD4 in mice resulted in an elevation of myelin thickness in sciatic nerves,” the article’s authors indicated, who added that blocking HDAC3 for too long could allow myelin to overgrow and cause excessively thick insulation.
Translating data in the current study to clinical application in human patients will require extensive additional research, Dr. Lu stated. Now that the prospective therapy has been successfully tested in mice, researchers are exploring additional research in animal models that more closely mimic the repair of injured peripheral nerves in humans. This includes looking specifically at some demyelinating diseases that affect the central nervous system, such as multiple sclerosis.