Team Discovers Molecular "Missing Link" Driving Nerve Cell Regrowth

Newswise — An enzyme called sAC helps spur the growth of nerve endings in the developing embryo, and might also be used to someday regrow these "axons" in adults paralyzed by spinal cord injury. The discovery, by a team of researchers at Weill Cornell Medical College in New York City, is reported in last month's issue of Nature Neuroscience. "Identifying soluble adenylyl cyclase (sAC) as a key player in axonal growth has been like finding a crucial 'missing link' in the biochemical chain that leads to nerve cell regeneration," explains study senior author Dr. Samie Jaffrey, associate professor of pharmacology at Weill Cornell Medical College. "With this new piece of the puzzle, we can begin serious work on introducing sAC directly into damaged spinal cords, where we hope it will encourage axons to seek out vital new connections. The ultimate goal is a treatment that can prevent paralysis or restore movement to paralyzed individuals," he says. The discovery may also have implications for the treatment of other conditions characterized by impaired axonal growth, such as certain developmental disorders and diabetes-linked damage to peripheral nerves. sAC has had a long association with Weill Cornell ever since two of the Medical College's noted pharmacology researchers, Drs. Jochen Buck and Lonny Levin, first identified the enzyme 8 years ago. These two investigators (both of whom are listed as co-authors on the current paper) also discovered that high levels of sAC are essential to the activation of another biochemical growth "switch" called cyclic AMP (cAMP). "cAMP turns axonal growth on or off," explains study lead author Karen Y. Wu, a graduate student in the Department of Pharmacology at Weill Cornell. "During embryonic and fetal development, there's a lot of cAMP around. That pushes new nerves to grow, reach out and make necessary connections." However, adult nerve cells -- which typically lack the ability to form new connections -- have only miniscule amounts of cAMP. "We knew that high levels of cAMP helped spur axonal growth in developing cells. But what was the physiologic signal that triggered cAMP production? That was the real puzzle," Wu says. "We wondered if this new molecule, sAC, might be present and active around nerve growth cones -- the tiny 'buds' at the tip of the axon that direct its growth." The experiments she and Dr. Jaffrey conducted found that it was. Observing the development of nerve cells derived from embryonic rats, the researchers first determined that sAC was expressed in high amounts by developing rat axons. They then used pharmacologic and genetic techniques to remove sAC from around the axons' growth cones. "When we took sAC away, the axons suddenly failed to grow," says Dr. Jaffrey. "In fact, without sAC, these embryonic axons began to resemble axons in injured adult spinal cords -- axons that were incapable of growth." Reversing the experiment, they used similar techniques to overexpress sAC, flooding nerve growth cones with the enzyme. "The result: accelerated axonal growth," according to Wu. The discovery fills in a crucial step in the biochemical "chain of command" that fosters axonal growth, the researchers say. Here's how they believe it works: First, proteins that promote axonal outgrowth, such as a signaling molecule called netrin-1, boost levels of calcium around the growth cone. This sudden rise in calcium is the "go" signal for sAC, which triggers the production of cAMP. High levels of cAMP are a signal to axons that growth can begin. "Now that we know the major steps involved in this process, we hope to replicate it using gene therapy approaches at the site of spinal cord injury," explains Dr. Jaffrey. His team's next step: introducing sAC to adult axons via a harmless virus that is genetically designed to home in on nerve growth cones. The virus would then express sAC in large quantities at the site. "Hopefully, you'd get a physiologically relevant boost in cAMP, in the same way that developing axons normally experience it in the embryo," Wu says. "The result, we hope, would be axonal regrowth and some restoration of nerve function and movement." These laboratory experiments could begin in the relatively near future, she says. The ultimate goal is an injected therapy that might help patients with spinal cord injury avoid paralysis, or help those already paralyzed regain function. "I really think that there will someday be gene therapy along these lines, with agents like sAC introduced to the site of injury to spur regeneration. This would be especially useful in that really critical period right after an accident," Dr. Jaffrey says. The findings also deepen our understanding of healthy and unhealthy neuronal development, the researchers say. "For example, certain fetal and childhood developmental disorders are closely associated with impaired axonal growth," Dr. Jaffrey says. "While we're a long way off from effective prevention or treatment for many of these disorders, this new discovery points the way to important new avenues of research." This work was funded by grants from the U.S. National Institutes of Health, the Christopher Reeve Paralysis Foundation, the Barbara and Stephen Friedman Fellowship Endowment, the American Diabetes Association, the Hirschl Weill-Caulier Trust, and the Ellison Medical Foundation. Co-authors include Jonathan H. Zippin, David R. Huron, Margarita Kamenetsky and Ulrich Hengst -- all of Weill Cornell Medical College in New York City.