Presently damaged nerve fibers (or axons) from spinal nerves do not regenerate and there are no good ways to repair them. However, a new set of experiments suggest that the repair of these nerves might be possible after spinal cord injury or brain trauma.
Researchers from Imperial College London and the Hertie Institute, University of Tubingen, Germany, have identified a possible mechanism for re-growing damaged central nervous system nerve fibers. Such damage causes loss of sensation and permanent paralysis. However, regenerating nerve fibers is one of the best hopes for those suffering from CNS damage to recover.
This work was published in the journal Nature Communications, and this work trades on the function of a protein called P300/CBP-associated factor (PCAF). PCAF seems to be essential for the cellular pathway that damaged neurons use to properly regenerate. When PCAF was injected into mice with damage to their central nervous systems, the injected mice showed significant increases in the number of nerve fibers that regenerated. This indicates that it might be possible to chemically control the regeneration of nerves in the CNS.
“The results suggest that we may be able to target specific chemical changes to enhance the growth of nerves after injury to the central nervous system,” said lead study author Professor Simone Di Giovanni, from Imperial College London’s Department of Medicine. “The ultimate goal could be to develop a pharmaceutical method to trigger the nerves to grow and repair and to see some level of recovery in patients. We are excited about the potential of this work but the findings are preliminary.
“The next step is to see whether we can bring about some form of recovery of movement and function in mice after we have stimulated nerve growth through the mechanism we have identified. If this is successful, then there could be a move towards developing a drug and running clinical trials with people. We hope that our new work could one day help people to recover feeling and movement, but there are many hurdles to overcome first,” he added.
Of particular interest to Dr. Di Giovanni and his colleagues was how axons in the peripheral nervous system (PNS) make a concerted effort to grow back when they are damaged, whereas CNS axons mount little or no effort. Damage to the peripheral nervous system is followed by regeneration of about 30% of the damaged nerves, accompanied by recovery of some movement and function. Could neurons in the central nervous system be coaxed into a similar behavior?
Co-author Dr. Radhika Puttagunta from the University of Tubingen said: “With this work we add another level of understanding into the specific mechanisms of how the body is able to regenerate in the PNS and have used this knowledge to drive regeneration where it is lacking in the CNS. We believe this will help further our understanding of mechanisms that could enhance regeneration and physical recovery after CNS injury.”
To investigate damage and regeneration in central and peripheral nervous systems, Di Giovanni and his group examined mouse models and cells in culture. They compared the responses to PNS damage and CNS damage in a type of neuron called a dorsal root ganglion, which connects to both the CNS and the PNS.
Interestingly, they discovered that epigenetic mechanisms were at the core of the regeneration capacity of these cells. Epigenetic mechanisms are processes that, without altering our DNA, manage to activate or deactivate genes in response to the environment, and are linked to changes in the way DNA is packaged within the cell. Epigenetic considerations control genes that influence the onset of diseases such as cancer and diabetes. However this is the first demonstration of a specific epigenetic mechanism responsible for nerve regeneration.
When nerves are damaged in the PNS, the damaged nerves send ‘retrograde’ signals back to the cell body to switch on an epigenetic program to initiate nerve growth. Very little was previously known about the mechanism which allows this ‘switching on’ to occur. When DiGiovanni’s group identified the signal transduction pathway that led to the ‘switching on’ of the program to initiate nerve regrowth, they discovered that PCAF was central to this process. Furthermore when they injected PCAF into mice with damage to their central nervous system, there was a significant increase in the number of nerve fibers that grew back.
Thus, PCAF is necessary for conditioning-dependent axonal regeneration and also promotes regeneration after spinal cord injury. Thus, PCAF is a part of a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, which also makes it and the protein with which it associates a novel target for clinical application.