Neurotoxin-mediated ­­potent activation of the axon degeneration regulator SARM1

  1. Andrea Loreto  Is a corresponding author
  2. Carlo Angeletti
  3. Weixi Gu
  4. Andrew Osborne
  5. Bart Nieuwenhuis
  6. Jonathan Gilley
  7. Peter Arthur-Farraj
  8. Elisa Merlini
  9. Adolfo Amici
  10. Zhenyao Luo
  11. Lauren Hartley-Tassell
  12. Thomas Ve
  13. Laura M Desrochers
  14. Qi Wang
  15. Bostjan Kobe
  16. Giuseppe Orsomando  Is a corresponding author
  17. Michael P Coleman  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. Polytechnic University of Marche, Italy
  3. University of Queensland, Australia
  4. Griffith University, Australia
  5. AstraZeneca, United States
  6. The University of Queensland, Australia

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. 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.

Data availability

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).

The following data sets were generated

Article and author information

Author details

  1. Andrea Loreto

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    al850@cam.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6535-6436
  2. Carlo Angeletti

    Department of Clinical Sciences (DISCO), Polytechnic University of Marche, Ancona, Italy
    Competing interests
    No competing interests declared.
  3. Weixi Gu

    School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    Weixi Gu, receives research funding from Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly and Co., Cambridge, MA, USA, but they had no role in the research presented here..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1185-3557
  4. Andrew Osborne

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Andrew Osborne, is affiliated with Ikarovec Ltd. The author has no financial interests to declare..
  5. Bart Nieuwenhuis

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2065-2271
  6. Jonathan Gilley

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9510-7956
  7. Peter Arthur-Farraj

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1239-9392
  8. Elisa Merlini

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  9. Adolfo Amici

    Department of Clinical Sciences (DISCO), Polytechnic University of Marche, Ancona, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1081-7749
  10. Zhenyao Luo

    School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    Zhenyao Luo, receives research funding from Disarm Therapeutics, a wholly- owned subsidiary of Eli Lilly and Co., Cambridge, MA, USA, but they had no role in the research presented here..
  11. Lauren Hartley-Tassell

    Institute for Glycomics, Griffith University, Southport, Australia
    Competing interests
    No competing interests declared.
  12. Thomas Ve

    Institute for Glycomics, Griffith University, Brisbane, Australia
    Competing interests
    Thomas Ve, Thomas Ve receives research funding from Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly & Co., Cambridge, MA, USA, but they had no role in the research presented here..
  13. Laura M Desrochers

    Neuroscience, BioPharmaceuticals R and D, AstraZeneca, Waltham, United States
    Competing interests
    Laura M Desrochers, This work is in part funded by a BBSRC/AstraZeneca Industrial Partnership Award and Laura M Desrochers was an employee of AstraZeneca for part of the project. Laura M Desrochers is affiliated with Vertex Pharmaceuticals. The author has no financial interests to declare..
  14. Qi Wang

    Neuroscience, BioPharmaceuticals R and D, AstraZeneca, Waltham, United States
    Competing interests
    Qi Wang, This work is in part funded by a BBSRC/AstraZeneca Industrial Partnership Award and Qi Wang was an employee of AstraZeneca for part of the project. Qi Wang is affiliated with Kymera Therapeutics. The author has no financial interests to declare..
  15. Bostjan Kobe

    School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia
    Competing interests
    Bostjan Kobe, receives research funding from Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly and Co., Cambridge, MA, USA, but they had no role in the research presented here..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9413-9166
  16. Giuseppe Orsomando

    Department of Clinical Sciences (DISCO), Polytechnic University of Marche, Ancona, Italy
    For correspondence
    g.orsomando@staff.univpm.it
    Competing interests
    No competing interests declared.
  17. Michael P Coleman

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    mc469@cam.ac.uk
    Competing interests
    Michael P Coleman, holds funding jointly provided by AstraZeneca for academic research and consults for Nura Bio, but they had no role in the research presented here..

Funding

Wellcome Trust (210904/Z/18/Z)

  • Andrea Loreto

Wellcome Trust (206634)

  • Peter Arthur-Farraj

Biotechnology and Biological Sciences Research Council (BB/S009582/1)

  • Andrea Loreto
  • Jonathan Gilley
  • Michael P Coleman

UNIVPM (RSA 2016-18 and 2017-19)

  • Giuseppe Orsomando

Australian National Health and Medical Research Council (NHMRC 1160570)

  • Bostjan Kobe

Sight Research UK (SAC 041)

  • 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.

Ethics

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.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Publication history

  1. Preprint posted: September 19, 2020 (view preprint)
  2. Received: August 5, 2021
  3. Accepted: December 5, 2021
  4. Accepted Manuscript published: December 6, 2021 (version 1)
  5. Version of Record published: January 13, 2022 (version 2)

Copyright

© 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.

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  1. Andrea Loreto
  2. Carlo Angeletti
  3. Weixi Gu
  4. Andrew Osborne
  5. Bart Nieuwenhuis
  6. Jonathan Gilley
  7. Peter Arthur-Farraj
  8. Elisa Merlini
  9. Adolfo Amici
  10. Zhenyao Luo
  11. Lauren Hartley-Tassell
  12. Thomas Ve
  13. Laura M Desrochers
  14. Qi Wang
  15. Bostjan Kobe
  16. Giuseppe Orsomando
  17. Michael P Coleman
(2021)
Neurotoxin-mediated ­­potent activation of the axon degeneration regulator SARM1
eLife 10:e72823.
https://doi.org/10.7554/eLife.72823

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