Injuries are a part of life. In most cases, such as cuts, bruises, tears, and even broken bones, our bodies heal. But when damage occurs to the central nervous system – or as most people call it, CNS – the outlook can be heartbreaking. The cells in this area, known as neurons, simply are not good at regeneration. This is why damage to the spinal cord and retina is considered a dire ailment.
One of the consequences of CNS injury is the loss of connections between individual neurons. When this happens, much like an electrical circuit, the flow of energy is stopped. Restoring those biological links requires the regeneration of the branches of the neurons, known as axons. Unfortunately, figuring out how to convince these cells to accomplish the task represents a huge challenge.
One option involves changing the cell’s central command centre, the genome. Genetic alterations can induce the formation of axons. However, this particular approach is incredibly difficult and may not be useful.
Another approach is to add drugs to the cells. Once the neuron senses the molecules, it can be prompted to form these branches. For this to happen however, we must understand how certain chemicals lead to axon regeneration.
For the laboratory of Dr. Alyson Fournier at McGill University, the latter approach seemed to be the best way forward. Her group attempted to find one particular molecule capable of promoting regeneration of axons. Earlier this month, they reported in the journal Neuron their success in finding a potential candidate. It’s a natural chemical formed by fungi known as fusicoccin-A, or as it is generally called, FC-A.
Much like other drugs originating from fungi, such as antibiotics and statins, FC-A actually is a toxin for plants. In the wild, this molecule leads to damage in plants. The molecule accomplishes this by adhering to a particular type of protein, known cryptically as 14-3-3 . When this happens, the plant cells become open such that they lack proper structure and end up wilting.
Though this is not good news for the plant, for Fournier’s team, the ability of the molecule to target 14-3-3 proteins provided an opportunity. It turns out neurons need 14-3-3 proteins to grow axons. If the group was right, the use of FC-A on damaged neurons would end up forcing the cell to make those branches.
The experiments were relatively straightforward. The team cultured neurons from the brains of rats and then scratched them to cause injury. Next, they examined whether the addition of FC-A would result in axon regeneration. As expected, the chemical worked. The team also tried the same experiment on human fetal neurons and saw the same result. This meant they had found a possible candidate for repairing damaged neurons in the CNS.
While the results were promising, for Fournier’s team, the FC-A effect was only half of the story. They wanted to find out what was happening inside the cell to allow this regeneration. Using biochemical techniques, they identified a protein known as general control non-depressible 1, or GCN1. It’s involved in stress response and appeared to be involved in preventing axon regeneration. They determined that the combination of FC-A and 14-3-3 was neutralizing GCN1 and allowing the cell to move ahead with repair.
The team went back to the neuronal cultures, to find out whether GCN1 was the target. As expected, they were correct. The FC-A and 14-3-3 combination grabbed a hold of GCN1 and ensured it could not stop growth. This provided the other half they needed to move into the next stage with confidence. It was time to test FC-A in a mouse.
The experiment was simple. A portion of the spinal cord was injured and FC-A was injected into the area. The goal was to see regeneration of the axons. If their hopes were to be fulfilled, the mouse would begin to heal in comparison to controls.
With a single dose of FC-A in the spinal cord the neurons remained damaged. Yet the addition of FC-A did reduce the overall extent of injury to the axons. Although this wasn’t what they had hoped to see, the results suggested a singular treatment, while helpful, was not the answer.
Despite the disappointment, the team did not waver from their goal. They chose a less dramatic injury in the retina and added a second dose of FC-A after seven days. When this happened, they were rewarded. New axons were formed in the damaged area and the retina appeared to undergo repair. It was not quite what they hoped to see but it provided the evidence needed to underscore the potential of this fungal toxin.
Even with the encouraging results, don’t expect to see FC-A in clinics anytime soon. The results of this study are only preliminary. Far more research on the benefit of FC-A needs to be performed before this can be considered a possible treatment for CNS damage. Yet, the positive effect of FC-A in the retina and even the spinal cord provide us with a realistic option for repair without the concerns associated with genetic manipulation. With further testing in animals and possibly one day in humans, we finally may have an answer to one of human health’s greatest challenges.
Original research article
Kaplan A, Morquette B, Kroner A, Leong S, Madwar C, Sanz R, Banerjee SL, Antel J, Bisson N, David S, Fournier AE. Small-Molecule Stabilization of 14-3-3 Protein-Protein Interactions Stimulates Axon Regeneration. Neuron. 2017 Mar 8;93(5):1082-1093.e5. doi: 10.1016/j.neuron.2017.02.018.