Targeted molecules play only minor role in axon repair

June 9, 2010

Neuroscientists at the University of California, San Diego School of Medicine have found that removing three key inhibitory molecules from myelin - the insulating material that surrounds nerve cell fibers - does not significantly boost the ability of injured spinal axons to regenerate and restore themselves to full function.

"I think this just shows how incredibly complicated the challenge is to induce axon and functional recovery after (CNS) injuries," said Binhai Zheng, PhD, assistant professor of neurosciences at UC San Diego School of Medicine and principal investigator of the study. "It's not going to be one gene or one approach that proves to be the answer. Successful regeneration will likely require a combination of many approaches and techniques."

The findings, to be published by Zheng and colleagues in the June 10 issue of the journal Neuron, run contrary to a popular and enduring hypothesis that the elimination of key inhibitory molecules in myelin should measurably boost axon regeneration in CNS injuries. The idea has spurred much research in recent years and, in fact, underlies a current clinical trial in Europe testing the safety and efficacy of neutralizing one of three known myelin-associated inhibitors.

In lower animal species, such as fish and tailed amphibians, damaged spinal are capable of self-repair and regeneration. This is not true, however, in humans and other mammals. While the mammalian (such as nerves in the arms and legs) can repair damage and grow new connections, the central nervous system cannot. Serious trauma to the brain and spinal cord tends to be permanent, and often catastrophic.

The reason why the CNS cannot repair itself remains a fundamental mystery, but researchers have developed a handful of hypotheses, among them: the suppressive nature of scarring after the injury; insufficient growth-promoting factors or tissue bridges at the CNS injury site; the lack of intrinsic growth potential in and myelin-associated molecules that inhibit neuronal growth.

"There is work in all of these areas, but inhibitory molecules, especially those from myelin, have been the basis of the dominant theory for the last 20 years," said Zheng.

Myelin is a fatty material that sheathes the axons or connecting nerve fibers of neurons, insulating them from the surrounding environment. Though it is vital to the health and functioning of neurons, it also contains at least three molecules believed to inhibit new axon growth after injury in adult mammals. "The theory is that these molecules help stabilize growth after initial neuron development," said Zheng.

The three identified inhibitory molecules are Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). Some scientists have argued that if these molecules could be effectively countered or removed, a major obstacle to the regeneration of damaged spinal axons might disappear and a door opened to potential new therapies capable of restoring CNS functions.

The UCSD research, however, found that the absence of Nogo, MAG and OMgp did not significantly affect or improve regeneration in damaged axons in mouse models of spinal cord injury. Deleting any one of the inhibitory molecules did enhance compensatory sprouting in undamaged axons, but the sprouting did not result in associated behavioral improvements in the mice. Deleting all three inhibitors produced no synergistic effect at all.

Contrarily, recently published experiments elsewhere have reported some axonal growth and neurological recovery in a different mouse model lacking all three inhibitory molecules. Some regeneration was also noted in Nogo-deficient mice, but none in mice whose myelin lacked MAG or OMgp.

Jae K. Lee, PhD, lead author of the UCSD study and a postdoctoral fellow in Zheng's lab, said the different findings were not unusual for this kind of research, not completely surprising and might be explained by differences in experimental models and laboratory techniques. He said it remains possible, perhaps even likely, that myelin-associated inhibitory molecules contribute to inhibiting regeneration, but that it was also clear that targeting theses molecules alone is insufficient.

"Neutralizing these molecules won't be enough to promote functional regeneration," said Lee. "They are part of a much bigger and more complicated process. By better understanding their role, we get closer to understanding the entire mechanism of regeneration. Sometimes you have to eliminate parts of the process to get to the point where you can focus on the parts that can really effect change."

Explore further: Enabling nerve regeneration means evicting the cleanup crew

Related Stories

Enabling nerve regeneration means evicting the cleanup crew

February 28, 2007

Macrophages are the immune cells that engulf and destroy the debris of damaged tissue to enable the healing process to begin. Their presence at the scene of damage is critical, but once their task is complete, it is just ...

Promising new nanotechnology for spinal cord injury

April 2, 2008

A spinal cord injury often leads to permanent paralysis and loss of sensation below the site of the injury because the damaged nerve fibers can't regenerate. The nerve fibers or axons have the capacity to grow again, but ...

Researchers regenerate axons necessary for voluntary movement

April 6, 2009

For the first time, researchers have clearly shown regeneration of a critical type of nerve fiber that travels between the brain and the spinal cord and which is required for voluntary movement. The regeneration was accomplished ...

Finding the Right Connection after Spinal Cord Injury

August 2, 2009

In a major step in spinal cord injury research, scientists at the University of California, San Diego School of Medicine have demonstrated that regenerating axons can be guided to their correct targets and re-form connections ...

Regeneration can be achieved after chronic spinal cord injury

October 28, 2009

Scientists at the University of California, San Diego School of Medicine report that regeneration of central nervous system axons can be achieved in rats even when treatment delayed is more than a year after the original ...

Recommended for you

How the finch changes its tune

August 3, 2015

Like top musicians, songbirds train from a young age to weed out errors and trim variability from their songs, ultimately becoming consistent and reliable performers. But as with human musicians, even the best are not machines. ...

Machine Translates Thoughts into Speech in Real Time

December 21, 2009

( -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.