A new way to look at brain injuries

HOUSTON -- (October 22, 2009) -- Neurons are structurally complex, with specific parts of the cell responsible for information input and other parts responsible for information output. When neurons lose the ability to distinguish between inputs and outputs, the nervous system stops working. In a report published today in The Journal of Neuroscience, researchers at Baylor College of Medicine and the University of Connecticut Health Center show that this is exactly what happens after nervous system injury.

"This is a new way to think about nervous system injuries," said Dr. Matthew N. Rasband, associate professor of neuroscience at Baylor College of Medicine and senior author of the paper. "We have found a new mechanism contributing to the inability of the nervous system to be repaired."

Earlier discovery of the role of ankyrinG

Previously, Rasband and his colleagues discovered that the protein ankyrinG builds a 'molecular fence' in neurons to maintain the distinction between dendrites (the parts of the cell responsible for information input) and axons (the part of the cell responsible for information output); ankyrinG is only found at the axon initial segment, the site where axons begin and dendrites end. Using genetic tricks, they removed this molecular fence, and saw that proteins normally only found in dendrites moved into axons. In effect, they discovered that loss of ankyrinG converted axons (output) into dendrites (input).

Finding the mechanism of destruction of ankyrinG

In the current study, they extend this previous work to show that nervous system injuries like stroke and nerve crush destroy ankyrinG, leading to neurons that cannot properly distinguish between their inputs and outputs. Although this damage is irreversible, Rasband's group determined the events leading up to destruction of ankyrinG. They found that after injury, an enzyme gets activated and functions like molecular scissors, cutting ankyrinG into smaller, non-functional pieces. Rasband and his colleagues saw that discovery as a window of opportunity to use inhibitors of the enzyme to stop the degradation.

"We were successful, but only if the enzyme was inhibited before it destroyed ankyrinG."

Making use of and building on this knowledge

Rasband suggested that their results point to the need for multifaceted treatments for brain injuries and stroke that focus not only on neuroprotection, but also preserving the axon initial segment and maintaining the distinction between axons and dendrites.

Another step forward will be to determine if degradation of ankyrinG is a common event in a variety of brain and spinal cord injuries. With a grant from the Department of Defense, Rasband's group is currently studying traumatic brain injury to determine if blast injuries like those experienced by soldiers might also lead to damage of the axon initial segment.

Others who took part in the study include first author Dr. Dorothy P. Schafer, a former graduate student of Rasband who is now with Harvard Medical School; Dr. Smita Jha, a postdoctoral fellow in Dr. Rasband's laboratory in the department of neuroscience at BCM; Dr. Fudong Liu, Trupti Akella and Dr. Louise D. McCullough, all of the department of neuroscience at the University of Connecticut Health Center.

The research was supported by grants from the National Institutes of Health, the Department of Defense, the Dr. Miriam and Sheldon Adelson Medical Research Foundation and Mission Connect.

The full article is available at http://www.jneurosci.org/.

For more information on basic science at Baylor College of Medicine, please go to www.bcm.edu/fromthelab or www.bcm.edu/news.