Sci. Aging Knowl. Environ., 25 February 2004
Inflammation gives neurons a shove when a cellular brake releases
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/8/nf22
Taking off a car's parking brake won't necessarily start the vehicle rolling. Similarly, releasing a neuron's brake isn't enough to get it growing, a new study reveals. The results suggest that multiple signals must combine to maximize neuron growth after an injury.
Head injury, stroke, and neurodegenerative diseases kill neurons. Researchers want to refurbish broken brains by provoking cells to grow and rewire. But the brain contains molecules that hinder the process, such as a protein called Nogo, a component of the myelin insulating layer around nerves. The results of shackling Nogo have been mixed. Last year, two groups found that rodents lacking Nogo regenerate neurons to a limited degree, but another group found no regrowth (see "Go or No-Go"). Those observations suggested that growth might also require activation signals, but no one had tested the idea in animals.
To investigate, neuroscientist Dietmar Fischer and colleagues at Harvard Medical School in Boston exploited a previous observation. After researchers crush the optic nerve in mice, more neurons recover when animals also receive a lens injury, which apparently ignites particular immune cells that stimulate growth. The researchers determined whether cutting Nogo activity and inciting inflammation might fertilize more growth than either does individually.
The researchers tweaked Nogo function by manipulating its cell-surface receptor. They injected some mice with a virus that carries the normal gene for the receptor, thus supplementing cells' supplies of the protein. Other animals received a virus with a clipped version of the receptor gene; the resulting protein grabs Nogo but can't relay its signal. The remaining animals received a virus with no gene. The scientists crushed the animals' optic nerves and punctured the lenses of half the animals in each group. Two weeks later, they examined the nerves for signs of renewal. Animals with the altered receptor and a lens wound grew three times as many neurons as did animals with a dummy virus and the injury and sprouted 75 times as many neurons as did animals with supplemental normal Nogo and the injury. Neurons didn't grow when animals received mutant receptor but didn't suffer a lens wound. The study suggests that "you have to activate the growth program of neurons, and you have to overcome the inhibiting effects of myelin," says Fischer.
The study bolsters the idea that "inhibitory proteins aren't the only things that are important," says neuroscientist Lisa McKerracher of the University of Montreal, Canada. "Not everyone appreciates that." Still, a small percentage of neurons grew, and they extended only a short distance, she cautions. Cells would need to traverse several centimeters to restore the optic nerve. But in the spinal cord, a modest amount of growth might be enough to get neurons to detour around a wound and make new connections, McKerracher adds. Researchers should seek the molecules that prompt growth after lens injury, she says. Such efforts might reveal how to get damaged neurons rolling again.
February 25, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150