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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progresses relentlessly from a subtle decline in motor function to lethal respiratory paralysis within a few years of diagnosis (Pasinelli and Brown, 2006; Taylor et al, 2016)
Because denervation of the diaphragm muscle is responsible for lethal respiratory paralysis, we focused our analysis on innervation of this muscle
We found no significant difference in the amplitude of the first compound muscle action potentials (CMAPs) between SOD1-G93A mice injected with the MuSK agonist antibody or the control antibody to GP120
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progresses relentlessly from a subtle decline in motor function to lethal respiratory paralysis within a few years of diagnosis (Pasinelli and Brown, 2006; Taylor et al, 2016). The detachment of motor nerve terminals and withdrawal of motor axons has received less attention than the later loss of motor neurons, but therapeutic approaches designed to preserve neuromuscular synapses have the potential to maintain motor function, especially during the early phases of disease, and provide benefit to the quality of life for patient and family. Transgenic mice bearing dominant mutations in the human SOD1 gene, including SOD1-G93A mice, recapitulate the hallmark features of ALS and provide the most thoroughly studied animal model for ALS (Vinsant et al, 2013a; Vinsant et al, 2013b). Because detachment of motor nerve terminals is the primary cause for paralysis in SOD1-G93A mice, SOD1-G93A mice represent a clinically relevant model for ALS
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