1. Neuroscience
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Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody

  1. Sarah Cantor
  2. Wei Zhang
  3. Nicolas Delestrée
  4. Leonor Remédio
  5. George Z Mentis
  6. Steven J Burden  Is a corresponding author
  1. New York University School of Medicine, United States
  2. Columbia University, United States
Research Article
  • Cited 34
  • Views 3,603
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Cite this article as: eLife 2018;7:e34375 doi: 10.7554/eLife.34375

Abstract

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated SOD1-G93A mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of SOD1-G93A mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle.

Article and author information

Author details

  1. Sarah Cantor

    Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  2. Wei Zhang

    Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  3. Nicolas Delestrée

    Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  4. Leonor Remédio

    Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1509-0024
  5. George Z Mentis

    Center for Motor Neuron Biology and Disease, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  6. Steven J Burden

    Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States
    For correspondence
    steve.burden@med.nyu.edu
    Competing interests
    Steven J Burden, holds a patent (#9,329,182) for 'Method of treating motor neuron disease with an antibody that agonizes MuSK'.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3550-6891

Funding

ALS Association

  • Steven J Burden

National Institute of Neurological Disorders and Stroke (R37 NS36193)

  • Steven J Burden

National Institute of Neurological Disorders and Stroke (RO1 NS078375)

  • George Z Mentis

National Institute of Neurological Disorders and Stroke (T32 NS86750)

  • Sarah Cantor

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 procedures were approved and mice were maintained according to Institutional Animal Use and Care Committee (IACUC protocol number 160425) guidelines at NYU Medical School.

Reviewing Editor

  1. Jonathan Glass, Emory University, United States

Publication history

  1. Received: December 14, 2017
  2. Accepted: February 2, 2018
  3. Accepted Manuscript published: February 20, 2018 (version 1)
  4. Accepted Manuscript updated: February 20, 2018 (version 2)
  5. Accepted Manuscript updated: February 22, 2018 (version 3)
  6. Version of Record published: March 5, 2018 (version 4)
  7. Version of Record updated: June 7, 2018 (version 5)

Copyright

© 2018, Cantor 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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