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. 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 the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet know 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.
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-7 and figure supplements. VMN-bound dSARM1ARM crystal structure has been deposited in the Protein Data Bank (PDB: 7M6K).
VMN-bound dSARM1ARM crystal structureProtein Data Bank, 7M6K.
- Andrea Loreto
- Peter Arthur-Farraj
- Andrea Loreto
- Jonathan Gilley
- Michael P Coleman
- Giuseppe Orsomando
- Bostjan Kobe
- Andrew Osborne
- Bart Nieuwenhuis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All studies conformed to the institution's ethical requirements in accordance with the 1986 Animals (Scientific Procedures) Act under Project Licences PPL P98A03BF9 and PP1824519, and in accordance with the Association for Research in Vision and Ophthalmology's Statement for the Use of Animals in Ophthalmic and Visual Research.
- Moses V Chao, New York University Langone Medical Center, United States
© 2021, Loreto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.