Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
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.
Metrics
-
- 4,722
- views
-
- 825
- downloads
-
- 63
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, KA), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected, the models become less robust as the extent of the changes increases. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.
-
- Neuroscience
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.