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

Author:

Cantor Sarah1ORCID,Zhang Wei1,Delestrée Nicolas2,Remédio Leonor1ORCID,Mentis George Z2,Burden Steven J1ORCID

Affiliation:

1. 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

2. Center for Motor Neuron Biology and Disease and Departments of Pathology and Cell Biology and Neurology, Columbia University, New York, 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.

Funder

ALS Association

National Institute of Neurological Disorders and Stroke

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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