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Elife. 2018 Feb 20;7. pii: e34375. doi: 10.7554/eLife.34375.

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

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Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, New York, United States.
Center for Motor Neuron Biology and Disease and Departments of Pathology and Cell Biology and Neurology, Columbia University, New York, United States.


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.


MuSK; agonist antibody; amyotrophic lateral sclerosis; motor neuron; mouse; neurodegeneration; neuromuscular disease; neuroscience

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