Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.
Desrochers, Laura M
eLife Sciences Publications, Ltd
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Loreto, A., Angeletti, C., Gu, W., Osborne, A., Nieuwenhuis, B., Gilley, J., Merlini, E., et al. (2021). Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.. Elife, 10 https://doi.org/10.7554/eLife.72823
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.
biochemistry, chemical biology, mouse, neuroscience
Biotechnology and Biological Sciences Research Council (BB/S009582/1)
Wellcome Trust (210904/Z/18/Z)
Wellcome Trust (UNS38871)
National Eye Research Centre (SAC 041)
External DOI: https://doi.org/10.7554/eLife.72823
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331634
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/