Abstract Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1 (sterile alpha and TIR motif-containing protein 1). Here, we report vacor mononucleotide (VMN), a metabolite of the pesticide and neurotoxin vacor, as the most potent yet SARM1 activator. Removal of SARM1 shows complete rescue from vacor-induced neuron and axon death in vitro and in vivo . We present the crystal structure of VMN bound to the Drosophila SARM1 regulatory armadillo-repeat domain, thus facilitating drug development to prevent SARM1 activation in human disease. This study indicates the likely mechanism of action of vacor as a pesticide and lethal neurotoxin in humans, provides important new tools for drug discovery, and further demonstrates that SARM1 removal can permanently block programmed axon death specifically induced by toxicity as well as genetic mutation.

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity