SARM1 activation triggers axon degeneration locally via NAD+ destruction

Josiah Gerdts, E. J. Brace, Yo Sasaki, Aaron DiAntonio, Jeffrey Milbrandt

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD+) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD+, whereas SARM1-induced axon destruction could be counteracted by increased NAD+ synthesis. SARM1-induced depletion of NAD+ may explain the potent axon protection in Wallerian degeneration slow (Wlds) mutant mice.

Original languageEnglish
Pages (from-to)453-457
Number of pages5
JournalScience
Volume348
Issue number6233
DOIs
StatePublished - Apr 24 2015

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