A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration

Abstract

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to stress. NAD+ depletion triggers axonal degeneration, which is a characteristic feature of neurological diseases. Notably, loss of SARM1 is protective in murine models of peripheral neuropathy and traumatic brain injury. Herein, we report that citrate induces a phase transition that enhances SARM1 activity by ~2000-fold. This phase transition can be disrupted by mutating a residue involved in multimerization, G601P. This mutation also disrupts puncta formation in cells. We further show that citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (TIR-1). Notably, citrate induces the formation of larger puncta indicating that TIR-1/SARM1 multimerization is essential for degeneration in vivo. These findings provide critical insights into SARM1 biology with important implications for the discovery of novel SARM1-targeted therapeutics.

Data availability

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

Article and author information

Author details

  1. Heather S Loring

    Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Victoria L Czech

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Janneke D Icso

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lauren O'Connor

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sangram S Parelkar

    Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alexandra B Byrne

    Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7449-9188
  7. Paul R Thompson

    Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Paul.Thompson@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1621-3372

Funding

National Institute of General Medical Sciences (R35 GM118112)

  • Paul R Thompson

National Institute of Neurological Disorders and Stroke (F31 NS108610)

  • Heather S Loring

National Institute of Neurological Disorders and Stroke (R01 NS110936)

  • Alexandra B Byrne

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

Reviewing Editor

  1. Hening Lin, Cornell University, United States

Version history

  1. Received: January 19, 2021
  2. Accepted: June 6, 2021
  3. Accepted Manuscript published: June 29, 2021 (version 1)
  4. Version of Record published: July 8, 2021 (version 2)

Copyright

© 2021, Loring 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. Heather S Loring
  2. Victoria L Czech
  3. Janneke D Icso
  4. Lauren O'Connor
  5. Sangram S Parelkar
  6. Alexandra B Byrne
  7. Paul R Thompson
(2021)
A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration
eLife 10:e66694.
https://doi.org/10.7554/eLife.66694

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https://doi.org/10.7554/eLife.66694

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