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

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, includingSOD1-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 treatedSOD1-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 ofSOD1-G93Amice. 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.
Source: eLife - Category: Biomedical Science Tags: Neuroscience Source Type: research