Scientists have long puzzled over nerve regeneration. Damaged nerves in the arms or legs often repair themselves after injury, but those in the brain or spine rarely do. Research in the past 2 decades has suggested that GAP-43, a compound in the growth-associated protein family, influences nerve regrowth. But in laboratory trials, injured animals induced to produce extra amounts of this compound show only meager signs of spinal cord repair. Another compound under investigation, a cortical-actin-associated protein, CAP-23, has also performed feebly.
However, a study in mice shows that when unleashed simultaneously on a severed nerve that leads into the spinal cord, the two proteins multiply their effect, researchers report in the January Nature Neuroscience. GAP-43 and CAP-23 together induce up to 60 times as much nerve regrowth as either engenders alone, says coauthor J.H. Pate Skene, a neurobiologist at Duke University Medical Center in Durham, N.C. The results suggest that the two proteins might be used to repair spinal cord injuries in people, he says.
Axons, the long fibers that extend from nerve cells, produce GAP-43 and CAP-23 during early nerve development. Genes encoding the proteins switch off once the nerve cells are fully formed. However, the genes become active again after injury to so-called peripheral nerves, which lie outside the brain and spinal cord. The same reawakening doesn't happen in the brain or spinal cord—the central nervous system (CNS).
Skene and his colleagues genetically engineered six mice to produce the two proteins continuously. Four other mice made only one protein or the other. Five mice were genetically unaltered.
For each mouse, the scientists then severed a CNS nerve at the point where it enters the spinal cord. Because the fatty sheath that surrounds CNS axons inhibits axon regrowth, the researchers also grafted a piece of peripheral nerve into the gap created by the severed nerve in each mouse. This provided a conduit in which the severed axons might grow.
In the mice producing both proteins, 7 percent of axons grew the full, 5-millimeter length of the peripheral nerve transplant. However, in mice that manufactured only one or neither of the proteins, no axons traversed the full length of the peripheral nerve graft.
The researchers are currently examining whether the axons that regrow eventually hook up with their severed end, Skene says.
The axon growth "is potentially very exciting," says Patricia F. Maness, a neuroscientist at the University of North Carolina School of Medicine in Chapel Hill. The synergy that allows the proteins to work together but not singly may arise because the pair activates one or more genes not yet identified, she says.
Skene says that his team's work needs to be combined with other research that seeks to determine a mix of chemicals that provides an environment conducive to nerve regrowth.
Meanwhile, scientists need to establish whether the proteins can spur axon elongation without the help of a peripheral nerve graft, Clifford J. Woolf of Harvard Medical School in Boston says in the same issue of Nature Neuroscience.
J.H. Pate Skene
Department of Neurobiology
Duke University Medical Center
Durham, NC 27710
Clifford J. Woolf
Massachusetts General Hospital
Harvard Medical School
149 13th Street
Charlestown, MA 02129
Patricia F. Maness
University of North Carolina, Chapel Hill
Department of Biochemistry
Chapel Hill, NC 27599
Woolf, C.J., 2001. Turbocharging neurons for growth: Accelerating regeneration in the adult CNS. Nature Neuroscience 4(January):7.
Doster, S.K., A.M. Lozano, A.J. Aguayo, and M.B. Willard. 1991. Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury. Neuron 6:1.
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Travis, J. 1999. One injured nerve fiber heals another. Science News 155(June 5):358.