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
Affiliations
Tong Wu
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
Jian Zhu
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO 63114, USA
Amy Strickland
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
Kwang Woo Ko
Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110, USA
Yo Sasaki
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
Caitlin B. Dingwall
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
Yurie Yamada
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
Matthew D. Figley
Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110, USA
Xianrong Mao
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
Alicia Neiner
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA
A. Joseph Bloom
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO 63114, USA
Aaron DiAntonio
Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO 63114, USA; Corresponding author
Jeffrey Milbrandt
Department of Genetics, Washington University Medical School, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO 63114, USA; Corresponding author
Summary: 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.
