Protein May Offer Insights into Regenerating Brain Function After Injury

by Kayt Sukel

April 10, 2014

How well people recover after brain injury varies to a remarkable degree. Some of that, of course, is due to how and how badly they are hurt. A stroke may result in a very different type of damage than an improvised explosive device (IED) blast, and both will show different neurological losses than a blow directly to the head. But even two people with similar injuries will show differences in both the length and amount of functional recovery. New research from Duke University suggests understanding the neurobiological context of how neurons "re-wire" after injury may provide new clues into these differences-and perhaps improve the prognoses of brain-injured patients in the future.

Damaged dendrites

Neurons have a unique shape that helps them easily communicate with one another. The axon, a long thread-like fiber, extends from the soma, or cell body, conducting the electrochemical signal of the cell. Each neuron also has a number of dendrites, or shorter branch-like projections off the soma, that also both send and receive neurochemical signals to its neighbors. Theresa Jones, a neuroscientist at the University of Texas at Austin, says brain injury can make significant changes to the close signaling between cells, and some of those changes occur at the site of those smaller dendritic branches.

"After injury from a stroke, there is a lot going on that drives dendritic change. One is degenerative. Cells die from the stroke and so you lose those connections. But even cells that don't die off may lose a lot of their connections if neighboring cells die or the pathways are disturbed," she says. "The degeneration also is a natural signal to the brain that triggers regenerative responses in neurons. The axons that are left start throwing out new connections to the surviving dendrites. And the dendrites appear to remodel in concert with that."

That dendritic "remodeling" is part of what allows the injured brain to regain function over time. Chay Kuo, a neurobiologist at Duke University, wondered if a better understanding of the molecular processes underlying that remodeling might explain the differences doctors see from patient to patient after brain injury-and, perhaps, even help improve treatment.

"There's just not a whole lot known about it. Can a neuron lose its dendrites and then reliably regenerate them?  Can we find some way to help with that?" he asks. "Understanding how much can really be regenerated in a damaged brain area could, in fact, be very important for therapeutic strategies."

Looking to Drosophila

Kuo's team, including former graduate student Gray Lyons, looked at the neurons of Drosophila, the common fruit fly, to better understand dendritic regeneration because of a unique feature of these cells. Drosophila neurons naturally regenerate dendrites without the mess of injury.

As the organism grows from larvae to fly, its nervous system makes profound changes. Neurons shed their dendrites and then grow new ones in a completely different branching pattern, re-wiring its brain so it can focus on a flying insect's environment and needs, instead of a worm's. By examining this process, Kuo and Lyons discovered one protein, Cysteine proteinase-1 (Cp1), was in charge of regulating that second round of dendrite growth after shedding. When the team removed the protein, the fly lost its ability to regenerate dendrites after its metamorphosis from larvae to fly.

What's interesting about Cp1, according to Lyons, now a radiology resident at New York Presbyterian Hospital at the Cornell Medical Center, is that it acts in both the original development of dendrites and their later regeneration. But it works in different ways during each of those phases in Drosophila.

"The same protein does not work in the same way in both systems. In the fruit fly, Cp1 is using the same genes but in two very different ways and in two very different contexts to get two very different results. One version helps the neurons develop initially but does not help with regeneration. The other helps with the regeneration but not in development," he says.

The gene corresponding to Cp1 in mammals is lysosomal protein capthesin-L (Ctsl), which has been linked to cancer and other diseases. Because this gene has not mutated much during evolution, Kuo and Lyons think that its mechanisms are likely retained across species. That means it may play a similar role in dendrite development and regeneration in humans.

"What this tells me is that there is unlocked potential in our own bodies. Knowing that there are these context differences in one protein could be very useful for therapies one day," says Lyons. "We could, perhaps, find a way to get the body to react in a different way and use its own natural mechanisms to help with regeneration after injury."

Jones agrees that it is likely we could one day harness the body's natural regenerative processes to help foster better recovery after brain injury. Doctors already do it, she says, through their use of different rehabilitation strategies that reshape neural pathways after injury. They don't, however, understand all the neurobiological ins and outs of how it works. While she sees promise in the idea of helping regeneration along if we can, she offers the caveat that just adding molecules probably won't lead to optimal recovery.

"The trick is helping regeneration along in a way that promotes the right kind of brain plasticity. Because it's not enough to make the dendrites grow and make new synapses after injury. You need the dendrites to grow in the right way and the synapses to go in the right places so you can best restore function," she says. "And, ultimately, that's probably going to require that any neurobiological manipulations be coupled with behavioral training approaches. That's the way the brain works:  It responds and changes to behavior and experience."