Longevity Briefs: Is This Molecular Switch The Key To Repairing Damaged Nerves?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Compared to other tissues, the central nervous system has a limited ability to repair itself, meaning that when axons (the long nerve fibres that project from nerve cells to other areas of the body) get damaged, they struggle to regrow. Getting axons to regenerate is a major challenge in regenerative medicine and in ageing, since axons become easier to damage with advancing age. However, there is no reason why regenerating axons or even large parts of the nervous system wouldn’t be possible in theory, as many species such as Zebrafish (whose nervous systems are similar to ours in some ways) are able to regenerate their spinal cords and even parts of their brains.

Mammals generally lack this regenerative capacity for various reasons. Following injury, nerve cells activate mechanisms to resist cellular stress, but this comes at the expense of growth. However, the potential for these cells to grow is still there, and there may be ways to kick them into action. In this study, researchers identified what appears to be an important receptor that regulates the balance between stress resistance and growth, and that can be targeted to push axons towards growth.

The discovery:

Researchers were interested in the role of aryl hydrocarbon receptor, or AhR, in axon regeneration. This receptor resides inside the cell and acts as a ‘molecular switch’ that senses a wide range of environmental signals and moves to the cell nucleus in order to regulate gene expression in response. AhR bears similarities with other molecular switches thought to be involved in neuron repair, but the role of AhR specifically was has been under-explored.

In order to test the function of AhR, researchers first demonstrated that AhR could be chemically activated or suppressed in mouse neurons cultured in a dish. They then used small interfering RNA (a genetic technique that allows the activity of a specific gene to be suppressed) in order to suppress the levels of AhR inside mouse neurons. They found that when these neurons were cultured, the axons they grew were around 20% longer than controls, suggesting that AhR was suppressing neuron growth. Activating and suppressing AhR with chemicals further confirmed this finding, with activators shortening the axons while inhibitors lengthened them.

Treating living mice with a drug that suppressed AhR activation also resulted in longer axons. To test whether this could help boost nerve repair after injury, researchers developed genetically modified mice in which the gene encoding AhR could be deleted upon administration of a drug called tamoxifen. 11 mice were then given a sciatic nerve crush injury in their hind legs, and recovery was observed in the 6 mice in which AhR had been deleted vs the remaining 5 control mice. They found that AhR deletion mice had significantly more, longer regenerating axons at the injury site a few days post-injury. More importantly, this was correlated with functional improvements in how well the mice were able to use their injured limb 9 days post-injury. Similar observations were made for mice with spinal cord injury when AhR was deleted or when given a drug to suppress AhR activation.

The implications:

This research suggests that AhR is an important suppressor of axon growth in mammalian nerve cells, and that suppressing AhR can greatly enhance the regenerative capacity of nerves following injury in mice. Options following nerve injury in humans are relatively limited, and mostly geared towards promoting what little regenerative capacity the nervous system does have, and promoting the remapping of surviving nerves to maintain physical function. Therefore, any treatment that actually enhances nerve repair could be highly impactful for human health. Promoting axon growth might also be beneficial for cognitive function in the ageing brain. However AhR has important functions outside the central nervous system, including in detoxification by the liver and in the immune system, so suppressing AhR throughout the entire body probably wouldn’t be desirable.