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Molecule discovery may lead to new drugs for brain and spinal cord injury

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Molecule discovery may lead to new drugs for brain and spinal cord injury

A new study reveals that a small molecule produced by a fungus may stimulate the regeneration of axons - the slender, "thread-like projections that carry electrical signals" between nerve cells in the brain and spinal cord. The researchers believe that the discovery could lead to much needed new drugs that repair damage to the central nervous system.

Axon damage is a feature of injury to the central nervous system, such as that which occurs in traumatic brain injury, stroke, and spinal cord injury. It is the main reason for disability that results from these conditions.

Unfortunately, once they are damaged, axons do not regenerate easily. Also, recent research suggests that in the case of traumatic brain injury, axons can continue to degenerate even years after injury and may play a role in the development of Alzheimer's disease-like changes in the brain.

The new study - led by McGill University in Montreal, Canada, and published in the journal Neuron - concerns a family of proteins called 14-3-3 that show some ability to protect nerve cells or neurons.

 

Senior author Alyson Fournier, a professor of neurology and neurosurgery at McGill, heads a laboratory that has been investigating 14-3-3 and looking for ways to stimulate axon regeneration.

Axon damage affects millions of people

Every year in the United States, there are more than 1.5 million cases of traumatic brain injury, at an annual healthcare cost of over $60 billion.

Figures published by the Centers for Disease Control and Prevention (CDC) show that every year, more than 795,000 people in the U.S. have a stroke.

Stroke is the fifth leading cause of death in the overall population and the leading cause of serious long-term disability among U.S. adults; more than half of stroke survivors aged 65 and over experience reduced mobility following a stroke. The annual cost of stroke to the nation is estimated to be $33 billion - this includes the cost of healthcare, drugs, and missed work days.

According to the National Spinal Cord Injury Statistical Center, estimates from several studies suggest that the number of people in the U.S. living with spinal cord injury is between 243,000 and 347,000. The number of new cases per year is around 17,000.

Researchers found that a small molecule called fusicoccin-A stimulated regeneration of damaged axons. This image of the effect of treatment shows axons (stained greed) and the tips of growing axons, called growth cones (stained red). 
Researchers found that a small molecule called fusicoccin-A stimulated regeneration of damaged axons. This image of the effect of treatment shows axons (stained greed) and the tips of growing axons, called growth cones (stained red). 

 

Axon damage occurs not only in strokes and brain and spinal cord injuries, but also in many other diseases, including multiple sclerosis and a range of neurodegenerative disorders.

Starting point for drug development

During the researchers' investigation, first author Andrew Kaplan, a Ph.D. candidate in Fournier's group, came across a small molecule called fusicoccin-A that is produced by certain fungi. He found evidence that the molecule appears to stabilize interactions between 14-3-3 and other proteins in plants.

The discovery led the team to investigate whether the effect that fusicoccin-A has on the 14-3-3 proteins in plants also occurs in animals, as well as whether it could be used to harness the proteins to repair axons.

The researchers tested the idea by culturing mechanically damaged neurons with the molecule. Kaplan says that when he looked through the microscope the following day, "the axons were growing like weeds."

He and his colleagues conclude that their findings offer a starting point for developing drugs to treat axon damage. Kaplan suggests that future research should concentrate on discovering the underlying mechanisms through which fusicoccin-A stimulates axon repair.

"We have identified a novel strategy to promote axon regeneration with a family of small molecules that may be excellent candidates for future drug development. This is an exciting advance because the field has struggled to find treatments and identify targets for drugs that stimulate axon repair."
Prof. Alyson Fournier

In their investigation, the researchers uncovered one possible explanation concerning a protein called GCN1 that bonds to 14-3-3. They suggest that this bond could be an important factor in the ability of fusicoccin-A to stimulate axon growth, and further investigation may find that the bond could be a new target for therapies.

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