Editors' ChoiceNeuroscience

Clearing Away Injured Axons

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Science Signaling  31 Jul 2012:
Vol. 5, Issue 235, pp. ec200
DOI: 10.1126/scisignal.2003438

When an axon is damaged, the portion of the axon distal to the site of injury undergoes fragmentation and clearance, with the cell body and proximal axon remaining intact. The molecular mechanisms that control this form of injury-induced axonal death (Wallerian degeneration) appear to be distinct from those mediating apoptosis. In a screen for mutations that enabled long-term survival of severed olfactory receptor neurons, Osterloh et al. identified dsarm1, encoding the Drosophila adaptor protein sterile alpha and Armadillo motif 1, as required cell autonomously for Wallerian degeneration in the fruit fly. Whereas severed axons in wild-type flies disappeared completely within a week of injury, axons of neurons homozygous for any one of three dsarm1 loss-of-function mutations persisted for several weeks after severing. In flies, dsarm1 was widely expressed in larval neurons and was dispensable for neural development and pruning and for apoptotic cell death. In experiments with cultured mouse neurons, axons of those cultured from wild-type mice degenerated within 8 hours after severing, but those from Sarm1–/– mice persisted for up to 72 hours. In vivo, severed sciatic nerves degenerated within 3 days in wild-type mice but persisted for at least 14 days in Sarm1–/– mice. These persistent Sarm1–/– severed axons retained some myelination and mitochondria, had intact cytoskeleton and synapses, and were not infiltrated by macrophages. Human, mouse, and nematode Sarm1 homologs function as adaptor proteins that modulate Toll-like receptor signaling in innate immunity, with the nematode homolog Tir-1 also implicated in nonapoptotic cell death and neuronal differentiation. Because calcium (Ca2+) influx is required for Wallerian degeneration and Tir-1 functions in Ca2+ signaling in neurons, the authors propose that Sarm1 may couple Ca2 influx to axonal degeneration after injury.

J. M. Osterloh, J. Yang, T. M. Rooney, A. N. Fox, R. Adalbert, E. H. Powell, A. E. Sheehan, M. A. Avery, R. Hackett, M. A. Logan, J. M. MacDonald, J. S. Ziegenfuss, S. Milde, Y.-J. Hou, C. Nathan, A. Ding, R. H. Brown Jr., L. Conforti, M. Coleman, M. Tessier-Lavigne, S. Züchner, M. R. Freeman, dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337, 481–484 (2012). [Abstract] [Full Text]

X. M. Yu, L. Luo, dSarm-ing axon degeneration. Science 337, 418–419 (2012). [Abstract] [Full Text]

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