Abstract
Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure of the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet known is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation.
Highlights
46 Sterile alpha and TIR motif-containing protein 1 (SARM1) plays a central, pro47 degenerative role in programmed axon death (Osterloh et al, 2012)
The ratio between nicotinamide mononucleotide (NMN):nicotinamide adenine dinucleotide (NAD) is important to regulate SARM1 activity (Figley et al, 2021) and we have recently extended this to show that, at physiological levels, changes in NMN levels have the greater impact on the regulation of SARM1 activity 71 (Angeletti et al, 2021)
Here, we have investigated whether vacor, a disused pesticide and powerful neurotoxin associated with human peripheral and central nervous system disorders (Gallanosa et al, 1981; LeWitt, 1980) and axon degeneration in rats (Watson and Griffin, 1987), causes activation of programmed axon death
Summary
46 Sterile alpha and TIR motif-containing protein 1 (SARM1) plays a central, pro47 degenerative role in programmed axon death (including Wallerian degeneration) (Osterloh et al, 2012). We unexpectedly find that vacor metabolite VMN directly binds 84 to and activates SARM1, causing neuronal death.
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