1. Neuroscience
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Live imaging reveals the cellular events downstream of SARM1 activation

  1. Kwang Woo Ko
  2. Laura Devault
  3. Yo Sasaki
  4. Jeffrey Milbrandt  Is a corresponding author
  5. Aaron DiAntonio  Is a corresponding author
  1. Washington University School of Medicine, United States
Research Article
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Cite this article as: eLife 2021;10:e71148 doi: 10.7554/eLife.71148

Abstract

SARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here we used live imaging of mouse sensory neurons with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Kwang Woo Ko

    Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Laura Devault

    Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yo Sasaki

    Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0024-0031
  4. Jeffrey Milbrandt

    Washington University School of Medicine, St Louis, United States
    For correspondence
    jmilbrandt@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
  5. Aaron DiAntonio

    Washington University School of Medicine, St Louis, United States
    For correspondence
    diantonio@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7262-0968

Funding

National Institutes of Health (R01CA219866)

  • Jeffrey Milbrandt
  • Aaron DiAntonio

National Institutes of Health (RO1NS087632)

  • Jeffrey Milbrandt
  • Aaron DiAntonio

National Institutes of Health (RF1-AG013730)

  • Jeffrey Milbrandt

National Institutes of Health (F32NS117784)

  • Laura Devault

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Graeme W Davis, University of California, San Francisco, United States

Publication history

  1. Received: June 10, 2021
  2. Preprint posted: June 15, 2021 (view preprint)
  3. Accepted: November 12, 2021
  4. Accepted Manuscript published: November 15, 2021 (version 1)
  5. Version of Record published: November 24, 2021 (version 2)

Copyright

© 2021, Ko 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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