Nerve injury triggers an autodestruct program in axons, leading to their degeneration. Now, a new study (Science 337, 481–484) uncovers a suppressor of this pathway in mice and flies.

As a result of peripheral neuropathy or brain injury, the portion of an axon distal to the site of injury degenerates, in a process termed Wallerian degeneration. Whether this is a passive process due to the loss of trophic support or an active process that is induced upon injury remains unclear.

Credit: Francois Paquet-Durand / Photo Researchers, Inc.

Using a genetic screen of neurons from Drosophila mutants, Marc R. Freeman and his colleagues identified mutant axons that, when injured, did not degenerate. This protection was conferred by loss-of-function mutations in a gene termed dsarm (Drosophila sterile alpha and Armadillo motif).

In a mammalian model of sciatic nerve injury, axonal degeneration was reduced in mice deficient in the mouse ortholog of dsarm, Sarm1. In culture, Sarm1−/− neurons were also protected from degeneration upon axotomy. These same neurons, however, were not resistant to degeneration induced by other stressors, including growth factor deprivation, suggesting Wallerian degeneration is an active program induced in axons with injury. Although it remains unclear how Sarm1 is activated with injury and, downstream, how it activates degeneration, these findings suggest that Sarm1 could be targeted therapeutically to inhibit axonal degeneration.