The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila

  1. Arnau Llobet Rosell
  2. Maria Paglione
  3. Jonathan Gilley
  4. Magdalena Kocia
  5. Giulia Perillo
  6. Massimiliano Gasparrini
  7. Lucia Cialabrini
  8. Nadia Raffaelli
  9. Carlo Angeletti
  10. Giuseppe Orsomando
  11. Pei-Hsuan Wu
  12. Michael P Coleman
  13. Andrea Loreto
  14. Lukas Jakob Neukomm  Is a corresponding author
  1. University of Lausanne, Switzerland
  2. University of Cambridge, United Kingdom
  3. University Hospital of Geneva, Switzerland
  4. Polytechnic University of Marche, Italy

Abstract

Axon degeneration contributes to the disruption of neuronal circuit function in diseased and injured nervous systems. Severed axons degenerate following the activation of an evolutionarily conserved signaling pathway, which culminates in the activation of SARM1 in mammals to execute the pathological depletion of the metabolite NAD+. SARM1 NADase activity is activated by the NAD+ precursor nicotinamide mononucleotide (NMN). In mammals, keeping NMN levels low potently preserves axons after injury. However, it remains unclear whether NMN is also a key mediator of axon degeneration and dSarm activation in flies. Here, we demonstrate that lowering NMN levels in Drosophila through the expression of a newly generated prokaryotic NMN-Deamidase (NMN-D) preserves severed axons for months and keeps them circuit-integrated for weeks. NMN-D alters the NAD+ metabolic flux by lowering NMN, while NAD+ remains unchanged in vivo. Increased NMN synthesis, by the expression of mouse nicotinamide phosphoribosyltransferase (mNAMPT), leads to faster axon degeneration after injury. We also show that NMN-induced activation of dSarm mediates axon degeneration in vivo. Finally, NMN-D delays neurodegeneration caused by loss of the sole NMN-consuming and NAD+-synthesizing enzyme dNmnat. Our results reveal a critical role for NMN in neurodegeneration in the fly, which extends beyond axonal injury. The potent neuroprotection by reducing NMN levels is similar to the interference with other essential mediators of axon degeneration in Drosophila.

Data availability

Generated plasmids have been deposited in Addgene.All data generated or analyzed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Arnau Llobet Rosell

    Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7728-2999
  2. Maria Paglione

    Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Jonathan Gilley

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9510-7956
  4. Magdalena Kocia

    Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Giulia Perillo

    Department of Genetic Medicine and Development, University Hospital of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Massimiliano Gasparrini

    Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Lucia Cialabrini

    Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Nadia Raffaelli

    Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Carlo Angeletti

    Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Giuseppe Orsomando

    Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6640-097X
  11. Pei-Hsuan Wu

    Department of Genetic Medicine and Development, University Hospital of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Michael P Coleman

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Andrea Loreto

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6535-6436
  14. Lukas Jakob Neukomm

    Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
    For correspondence
    lukas.neukomm@unil.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5007-3959

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (176855)

  • Lukas Jakob Neukomm

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (211015)

  • Lukas Jakob Neukomm

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

  • Jonathan Gilley

International Foundation for Research in Paraplegia (P180)

  • Lukas Jakob Neukomm

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (190919)

  • Lukas Jakob Neukomm

Università Politecnica delle Marche (2018-20)

  • Giuseppe Orsomando

Wellcome Trust (210904/Z/18/Z)

  • Andrea Loreto

John and Lucille Van Geest Foundation

  • Michael P Coleman

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (201535)

  • Pei-Hsuan Wu

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

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Version history

  1. Preprint posted: January 30, 2022 (view preprint)
  2. Received: May 13, 2022
  3. Accepted: December 6, 2022
  4. Accepted Manuscript published: December 7, 2022 (version 1)
  5. Version of Record published: December 23, 2022 (version 2)

Copyright

© 2022, Llobet Rosell 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. Arnau Llobet Rosell
  2. Maria Paglione
  3. Jonathan Gilley
  4. Magdalena Kocia
  5. Giulia Perillo
  6. Massimiliano Gasparrini
  7. Lucia Cialabrini
  8. Nadia Raffaelli
  9. Carlo Angeletti
  10. Giuseppe Orsomando
  11. Pei-Hsuan Wu
  12. Michael P Coleman
  13. Andrea Loreto
  14. Lukas Jakob Neukomm
(2022)
The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila
eLife 11:e80245.
https://doi.org/10.7554/eLife.80245

Share this article

https://doi.org/10.7554/eLife.80245

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