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

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 ago...

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Autores principales: Cantor, Sarah, Zhang, Wei, Delestrée, Nicolas, Remédio, Leonor, Mentis, George Z, Burden, Steven J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837562/
https://www.ncbi.nlm.nih.gov/pubmed/29460776
http://dx.doi.org/10.7554/eLife.34375
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author Cantor, Sarah
Zhang, Wei
Delestrée, Nicolas
Remédio, Leonor
Mentis, George Z
Burden, Steven J
author_facet Cantor, Sarah
Zhang, Wei
Delestrée, Nicolas
Remédio, Leonor
Mentis, George Z
Burden, Steven J
author_sort Cantor, Sarah
collection PubMed
description 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.
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spelling pubmed-58375622018-03-07 Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody Cantor, Sarah Zhang, Wei Delestrée, Nicolas Remédio, Leonor Mentis, George Z Burden, Steven J eLife Neuroscience 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. eLife Sciences Publications, Ltd 2018-02-20 /pmc/articles/PMC5837562/ /pubmed/29460776 http://dx.doi.org/10.7554/eLife.34375 Text en © 2018, Cantor et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Cantor, Sarah
Zhang, Wei
Delestrée, Nicolas
Remédio, Leonor
Mentis, George Z
Burden, Steven J
Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title_full Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title_fullStr Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title_full_unstemmed Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title_short Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody
title_sort preserving neuromuscular synapses in als by stimulating musk with a therapeutic agonist antibody
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837562/
https://www.ncbi.nlm.nih.gov/pubmed/29460776
http://dx.doi.org/10.7554/eLife.34375
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