Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1
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).
-
VMN-bound dSARM1ARM crystal structureProtein Data Bank, 7M6K.
Article and author information
Author details
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.
Reviewing Editor
- Moses V Chao, New York University Langone Medical Center, United States
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.
Version history
- Preprint posted: September 19, 2020 (view preprint)
- Received: August 5, 2021
- Accepted: December 5, 2021
- Accepted Manuscript published: December 6, 2021 (version 1)
- 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.
Metrics
-
- 3,558
- views
-
- 658
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The articles in this special issue highlight how modern cellular, biochemical, biophysical and computational techniques are allowing deeper and more detailed studies of allosteric kinase regulation.