Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1

eLife

Giuseppe Orsomando¹  Adolfo Amici¹  Carlo Angeletti¹  Lauren Hartley-Tassell²  Thomas Ve²  Andrea Loreto³  Michael P Coleman³  Jonathan Gilley³  Peter Arthur-Farraj³  Bart Nieuwenhuis³  Andrew Osborne³  Elisa Merlini³  Qi Wang⁴  Laura M Desrochers⁴  Bostjan Kobe⁵  Weixi Gu⁵  Zhenyao Luo⁵ 

[1] Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Ancona, Italy;Institute for Glycomics, Griffith University, Southport, Australia;John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom;Neuroscience, BioPharmaceuticals R and D, AstraZeneca, Waltham, United States;School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia;

关键词: axon degeneration;    SARM1;    environmental neurotoxin;    vacor;    NAD;    VMN;    Mouse;   

DOI  :  10.7554/eLife.72823

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY