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Apr 2, 2014

Epigenetic Tickling May Stimulate CNS Repair

  • Curious as to why nerves of the peripheral nervous system (PNS) show some capacity for regrowth and repair, whereas nerves of the central nervous system (CNS) do not, scientists undertook a study of the PNS’ regenerative mechanisms, the chemical and genetic events that help peripheral nerves recover from injury. These scientists were already aware that damaged peripheral nerves emit “retrograde” signals, which activate an epigenetic program, which in turn initiates nerve growth. But the scientists were dissatisfied with how little was known about how, exactly, retrograde signaling could trigger the epigenetic mechanism.

    The scientists hoped that if more were understood about the trigger, which works in the PNS, they might learn how it could be made to work in the CNS. Then CNS damage, which is currently irreparable, might become amenable to treatment, and people suffering spinal cord injury, stroke, or brain trauma might avoid loss of sensation or permanent paralysis.

    Scientists representing Imperial College London and the Hertie Institute, University of Tuebingen compared the responses to PNS damage and CNS damage in a type of neuron called a dorsal root ganglion, which connects to both the PNS and the CNS. (The researchers considered cells in culture as well as mouse models.) Then, through systematic epigenetic studies, they discovered a protein that appears to be essential for a series of chemical and genetic events that allow nerves to regenerate.

    The details of this work appeared April 1 in Nature Communications, in an article entitled “PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.” As the title indicates, the crucial protein is called PCAF, for the histone acetyltransferase p300/CBP-associated factor. PCAF, the researchers found, “promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury.”

    When researchers injected PCAF into mice with damage to their central nervous system, this significantly increased the number of nerve fibers that grew back, indicating that it may be possible to chemically control the regeneration of nerves in the CNS.

    The researchers also found that extracellular signal-regulated kinase (ERK)-mediated retrograde signaling is required for PCAF-dependent regenerative gene reprogramming. “PCAF,” the authors wrote, “is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury.”

    One of the study’s authors, Radhika Puttagunta, Ph.D., from the University of Tuebingen, 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.”

    “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 Simone Di Giovanni, M.D., Ph.D., 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.”

    "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 toward 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.”



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