Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
- New York University School of Medicine, United States
- Columbia University, United States
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
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.
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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Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
eLife 7:e34375.
https://doi.org/10.7554/eLife.34375
