Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS

  1. Éric Martineau
  2. Adriana Di Polo
  3. Christine Vande Velde
  4. Richard Robitaille  Is a corresponding author
  1. Université de Montréal, Canada

Abstract

Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Using in vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously in SOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a contribution of neuromuscular factors extrinsic to motor neurons, with distal branches being more susceptible. These results show that NMJ denervation in ALS is a complex and dynamic process of continuous denervation and new innervation rather than a manifestation of sudden global motor neuron degeneration.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data has been provided for Figure 1, Figure 2 - Supplement 1, Figure 4, Figure 4 - Supplement 1, and Figure 5.

Article and author information

Author details

  1. Éric Martineau

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5503-0798
  2. Adriana Di Polo

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1430-0760
  3. Christine Vande Velde

    Département de neurosciences, Université de Montréal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Richard Robitaille

    Département de neurosciences, Université de Montréal, Montreal, Canada
    For correspondence
    richard.robitaille@umontreal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6628-0146

Funding

Canadian Institutes of Health Research (MOP-111070)

  • Richard Robitaille

Canadian Foundation for Innovation

  • Christine Vande Velde
  • Richard Robitaille

ALS Society of Canada (Doctoral Research Award)

  • Éric Martineau

Muscular Dystrophy Association

  • Christine Vande Velde

Fonds de Recherche du Québec - Santé

  • Christine Vande Velde

Robert Packard Center for ALS research

  • Richard Robitaille

Canadian Institutes of Health Research (PJT-152934)

  • Adriana Di Polo

ALS Society of Canada

  • Christine Vande Velde

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 experiments were performed in accordance with the guidelines of the Canadian Council on Animal Care, the Comité de Déontologie sur l'Expérimentation Animale of Université de Montréal (protocol #18-040) and the CRCHUM Institutional Committee for the Protection of Animals (protocol #N16008CVV and #N15047ADPs).

Reviewing Editor

  1. Don W Cleveland, University of California, San Diego, United States

Publication history

  1. Received: September 13, 2018
  2. Accepted: October 14, 2018
  3. Accepted Manuscript published: October 15, 2018 (version 1)
  4. Version of Record published: November 13, 2018 (version 2)

Copyright

© 2018, Martineau 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. Éric Martineau
  2. Adriana Di Polo
  3. Christine Vande Velde
  4. Richard Robitaille
(2018)
Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS
eLife 7:e41973.
https://doi.org/10.7554/eLife.41973

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