Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss

Tong Wu, Jian Zhu, Amy Strickland, Kwang Woo Ko, Yo Sasaki, Caitlin B. Dingwall, Yurie Yamada, Matthew D. Figley, Xianrong Mao, Alicia Neiner, A. Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here, we show the nicotinamide analog 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN, which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration, and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.

Original languageEnglish
Article number109872
JournalCell Reports
Volume37
Issue number3
DOIs
StatePublished - Oct 19 2021

Keywords

  • NAMPT
  • NMNAT
  • Vacor
  • base exchange reaction
  • mass spectrometry
  • metabolism
  • myelin
  • neurolytic block
  • sciatic nerve
  • tibial nerve

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