Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly

Lukas J. Neukomm, Thomas C. Burdett, Andrew M. Seeds, Stefanie Hampel, Jaeda C. Coutinho-Budd, Jonathan E. Farley, Jack Wong, Yonca B. Karadeniz, Jeannette M. Osterloh, Amy E. Sheehan, Marc R. Freeman

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Axon degeneration is a hallmark of neurodegenerative disease and neural injury. Axotomy activates an intrinsic pro-degenerative axon death signaling cascade involving loss of the NAD+ biosynthetic enzyme Nmnat/Nmnat2 in axons, activation of dSarm/Sarm1, and subsequent Sarm-dependent depletion of NAD+. Here we identify Axundead (Axed) as a mediator of axon death. axed mutants suppress axon death in several types of axons for the lifespan of the fly and block the pro-degenerative effects of activated dSarm in vivo. Neurodegeneration induced by loss of the sole fly Nmnat ortholog is also fully blocked by axed, but not dsarm, mutants. Thus, pro-degenerative pathways activated by dSarm signaling or Nmnat elimination ultimately converge on Axed. Remarkably, severed axons morphologically preserved by axon death pathway mutations remain integrated in circuits and able to elicit complex behaviors after stimulation, indicating that blockade of axon death signaling results in long-term functional preservation of axons. Neukomm and Burdett et al. identify the novel BTB/BACK domain molecule Axundead as required for axotomy-induced axon degeneration in Drosophila. axundead mutants provide long-term functional preservation of severed axons and block neurodegeneration induced by genetic activation of axon death signaling or blockade of NAD+ biosynthesis.

Original languageEnglish (US)
Pages (from-to)78-91.e5
JournalNeuron
Volume95
Issue number1
DOIs
StatePublished - Jul 5 2017

ASJC Scopus subject areas

  • Neuroscience(all)

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    Neukomm, L. J., Burdett, T. C., Seeds, A. M., Hampel, S., Coutinho-Budd, J. C., Farley, J. E., Wong, J., Karadeniz, Y. B., Osterloh, J. M., Sheehan, A. E., & Freeman, M. R. (2017). Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly. Neuron, 95(1), 78-91.e5. https://doi.org/10.1016/j.neuron.2017.06.031