Scientists present new treatment strategy for amyotrophic lateral sclerosis

Research suggests preserving neuromuscular synapses, which connect nerve and muscle and become disassembled during amyotrophic lateral sclerosis, could help treat the disease.
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Researchers from the New York University School of Medicine have described a new strategy for treating the neurodegenerative disorder amyotrophic lateral sclerosis (ALS).

Their study, published today in eLife, involves the use of a genetically engineered antibody to stimulate MuSK, a type of kinase essential for preserving neuromuscular synapses, which connect nerve and muscle and become disassembled during ALS. The findings open up the possibility of using a similar approach of maintaining synapses to potentially slow disease progression in patients with Alzheimer's, Parkinson’s, Huntington’s and other neurodegenerative disorders.

“ALS is a devastating disease that progresses quickly and aggressively, beginning with a subtle decline in motor function and culminating in lethal respiratory paralysis within a few years of diagnosis,” explains first author Sarah Cantor, PhD student at the New York University School of Medicine. “The loss of neuromuscular synapses occurs early during disease and is the primary cause of paralysis.

“We are only just beginning to understand the signalling pathways that control the attachment of nerve terminals to muscle. Two genes, Lrp4 and Musk, which are expressed by muscle, play important roles in this. We wanted to find out whether boosting signalling from the muscle back to nerve terminals, using a stimulatory antibody to MuSK, might slow the loss of neuromuscular synapses in a mouse model of ALS.”

Previous work has suggested that a specific type of antibody can stimulate MuSK in cultured muscle cells, but it had not been tested before in mice. Cantor and her team applied a single dose of this MuSK agonist antibody to ALS mouse models and found that it slowed denervation in the diaphragm muscle – the process behind respiratory paralysis in ALS patients – and improved motor neuron survival.

Next, they extended the treatment to see whether the antibody could preserve neuromuscular synapses over a longer period of time. The treatment indeed halted further synaptic loss and maintained synapses for at least 50 days after the mice displayed signs of disease.

“Following this, we were curious to see whether maintaining neuromuscular synapses and improving the output of the diaphragm muscle ultimately extended the lifespan of the mice,” explains senior author Steven Burden, PhD, Professor at the Skirball Institute of Biomolecular Medicine, and in the Department of Neuroscience and Physiology, and the Department of Cell Biology, at the New York University School of Medicine. “The female mouse models had an average lifespan of 169 days, while the males had 157.5 days. Prolonging the antibody treatment increased the survival of both sexes by seven days for the females and 10 days for males.”

Altogether, the findings present MuSK as a potential antibody treatment that decreases the detachment of motor nerve terminals from the muscle, improves the function of the diaphragm muscle and modestly extends survival in ALS mouse models, even when it is introduced after disease onset.

“This strategy targets a disease mechanism that is common to multiple types of ALS, namely the detachment of nerve terminals from the muscle, and is based on a therapeutic antibody format with considerable clinical significance,” Cantor concludes. “Our work suggests that combined disease interventions, including those that preserve neuromuscular synapses, could potentially improve the quality of life for many ALS patients.”


Along with Burden, this study was led by first author and PhD student Sarah Cantor, along with postdoctoral fellows Wei Zhang and Leonor Remédio, in the Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, NYU School of Medicine. Nicolas Delestrée, a postdoctoral fellow, and George Mentis, a faculty member at the Center for Motor Neuron Biology and Disease at Columbia University, were key collaborators.

The MuSK agonist antibody was produced and provided by Genentech.

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