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by Richard Saltus
Axon degeneration—an active process after injury—can be delayed.
A few days after injury, the axons in fruit flies disintegrate. However, in flies with mutations in a gene called dSarm, axons can last as many as 50 days after injury.
A mouse with a random mutation changed forever the way scientists think about how injured nerves die—and how, conceivably, their death might be delayed or prevented.
When the mouse’s long nerve fibers called axons were cut off from the nerve’s cell body (home to the nucleus) or crushed, the nerves survived up to 10 times longer than in normal mice—weeks instead of days—before disintegrating. This fluke of nature, dubbed the WldS mouse when it was discovered 20 years ago, showed that damaged nerves don’t simply starve to death from lack of nutrients, and that rapid death is not inevitable.
“This was serendipity at its finest,” says neuroscientist Marc Freeman, an HHMI early career scientist at the University of Massachusetts Medical School.
Excited about treating neurodegenerative diseases, such as Huntington’s, Parkinson’s, and Alzheimer’s, researchers began an immediate search for the WldS mutation’s protective powers. “If these diseases are caused by inappropriately activated pathways that promote degeneration, you might be able to block the pathways,” explains Freeman.
New treatments may be a distant prospect, but Freeman and colleagues have provided fresh insight into the function of the protein that blocks the nerve degeneration in that mouse variant, and they’ve found a gene that, when knocked out, duplicates the protective effect in other mouse strains.
“This is the first gene that can be knocked out to obtain the [characteristics] of the WldS mouse, and might point us to good targets for therapy,” he says.
The WldS mouse put a new spin on Wallerian degeneration, a process described in 1850 by British scientist Augustus V. Waller (WldS stands for “slow Wallerian degeneration”). Waller noted that severed frog axons showed no change for 24 to 36 hours. Then, the part of the axon cut off from the cell body explosively disintegrated, leaving a trail of debris that was quickly gobbled up by macrophages and other immune cells.
“Waller concluded that the axons died from a passive wasting away because they were starved of nutrients from the cell body,” Freeman says. But the prolonged survival of WldS axons suggested otherwise. “We have been taught that axons are highly dependent on the cell body,” he says. “But now we know they can be far more autonomous than we give them credit for.”
Image: Freeman Lab / University of Massachusetts Medical School