Loss of support from the cell body, of course, does eventually spell the end for damaged axons. But scientists now believe—and Freeman has offered direct evidence—that axons actively initiate their own degeneration through a process not unlike apoptosis, or programmed cell death, that rids the body of damaged cells. The WldS protein puts the brakes on the process.

The Death Trigger

In the April 10, 2012, issue of Current Biology, Freeman described a molecular chain of events that helps trigger degeneration of injured nerve axons in Drosophila—fruit flies. A focal point of the action, says Freeman, is the mitochondria—energy-generating organelles that shuttle back and forth along the nerve axon like trucks on a highway.

In normal Drosophila, Freeman reported, cutting a nerve caused a sudden surge of calcium ions into the axon. The flood of calcium stopped the mitochondria in their tracks, causing a power shortage within the axon and triggering its rapid degeneration.

But in fruit flies with the WldS mutation the researchers found, the WldS protein stemmed the injury-induced elevation of calcium in the axon. In addition, mitochondria remained mobile and continued to power the nerve fiber.

Yet this revelation, and other studies of WldS, didn’t directly identify a native self-destruct pathway that Freeman was looking for. And it didn’t chart a course for potential therapies: Adding the WldS protein or its components to millions of nerve cells is not a practical option. He continued to hunt for a smoking gun—a gene or protein that triggered axon degeneration and which might be blocked or knocked out with drug treatment.

The Freeman team’s discovery of the dSarm/Sarm1 gene, reported July 27, 2012, in Science, filled the bill on both counts. Screening for mutations in fruit flies, the researchers isolated mutants whose axons were intact as much as 50 days after injury. The mutation affects a gene called dSarm (“d” for Drosophila) that is required for Wallerian degeneration: the mutant form suppresses the degeneration.

In mice, a similar gene, Sarm1, proved to operate in the same way, and provides the first direct evidence, says Freeman, “that axons actively promote their own destruction after injury. The Sarm1 protein is a member of an ancient axon death-signaling pathway.” Both expression of the WldS protein and loss of the Sarm1 protein dramatically slow degeneration, but whether through related or separate mechanisms remains unclear.

“There is growing evidence that the biochemical pathway that triggers the degeneration of axons in response to injury overlaps with the pathways of degeneration in chronic disease,” adds HHMI alumnus Marc Tessier-Lavigne, president of Rockefeller University and a coauthor on the paper. “We’re excited that the discovery of a new entry point into that pathway has the potential to help devise novel approaches to treating neurodegenerative disease.”

The researchers are moving toward experimental therapies. “We’re working with collaborators to see if knocking out the Sarm1 gene in animal models of diseases like Huntington’s could moderate the symptoms,” says Freeman. “Our hope is that the answer is yes.”

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