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Nerve regeneration after central nervous system injury: Hope for the future
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A spinal cord injury or brain trauma often spells disaster for victims due to failure of central nervous system (CNS) nerve cells to regenerate axons, the nerve fibres that project from nerve cells and are essential for relaying information to other nerve cells. However, a new study from researchers in Imperial College London in the UK and the Hertie Institute in the University of Tuebingen in Germany may hold out hope for the future. In the study, published today in the journal Nature Communications, the researchers contrasted the inability of CNS nerves to regenerate to the situation in the peripheral nervous system (PNS). Injury to the PNS results in initiation of a programme of coordinated gene expression resulting in substantial nerve fibre regeneration. In the study, a protein called histone acetyltransferase p300/CBP-associated factor (PCAF) was identified as key to the PNS regeneration programme. When administered to mice with CNS injury, PCAF promoted significant nerve fibre regeneration.

The researchers used both in vivo mouse models and in vitro cell culture models to study the responses of a type of neuron known as a dorsal root ganglion to both CNS and PNS damage. Epigenetic changes in genes were focused on, i.e. alterations to gene activity caused by mechanisms that do not change the sequence of DNA. These are often chemical modifications such as acetylation or methylation. The researchers were interested in how in the PNS, damaged nerves are able to send ‘retrograde’ signals back to the cell body to instruct the cell to initiate epigenetic changes responsible for nerve regeneration.

The results showed that PCAF is central to this process as it promotes acetylation modifications at the promoters of established key regeneration-associated genes. However, this occurs only following a peripheral axonal injury, not a central nervous system injury. Importantly, injection of PCAF into mice with central nervous system damage resulted in a significant increase in nerve fibre re-growth.

Lead author on the study, Professor Simone Di Giovanni of Imperial College London explained the potential significance of this study for victims of central nervous system injuries when he said: "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….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.

Professor Di Giovanni added: "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."

Sources:

R. Puttagunta et al. 'PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system', Nature Communications (2014), doi: 10.1038/n-comms4527

Press release: Imperial College London; available at http://www.eurekalert.org/pub_releases/2...033114.php
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