Antibodies protect nerve-muscle connections in a mouse model of Lou Gehrig's disease

February 20, 2018

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes lethal respiratory paralysis within several years of diagnosis. There are no effective treatments to slow or halt this devastating disease. Mouse models of ALS reproduce the hallmarks of the disease, including a loss of nerve-muscle connections, called neuromuscular synapses, and a subsequent loss of nerve cells that connect to muscle, called motor neurons.

Now a new study led by NYU School of Medicine researchers identifies a novel treatment strategy that preserved neuromuscular synapses in a mouse model of aggressive ALS. Published February 20 in the journal eLife, the study found that the loss of such synapses was reduced in ALS mice injected with antibodies that stimulate a molecule in muscle which keeps nerves attached to the muscle.

By boosting the action of a protein called MuSK, the new approach slowed the loss of neuromuscular synapses, temporarily extended survival of motor neurons, and extended the lifespan of ALS mice.

"Our findings reveal a new therapeutic strategy for ALS that protects a pathway essential for keeping nerves and muscles connected," says Steven Burden, PhD, a professor in the Skirball Institute of Biomolecular Medicine, and in the Department of Neuroscience and Physiology, at NYU School of Medicine.

"There are few treatments for ALS, and the two FDA-approved drugs extend survival for only a few months in a subset of patients," says Burden. "We believe that our approach, mostly likely in combination with other drugs, may extend quality of life during the early phases of this disease."

Study Details

The results are based on the ability of neurons to pass messages to one another or to other targets, including skeletal muscle, at specialized junctions. Motor neurons connect to skeletal muscle at neuromuscular synapses, and the dismantling of these synapses is an early sign of disease in ALS. Although this dismantling is known to be a primary cause of ALS paralysis, most experimental treatments have sought to instead stop the death of motor neurons, which happens later in the disease course, researchers say.

The new approach centers on MuSK, a receptor tyrosine kinase on the muscle cell surface. Once stimulated by a signal provided by the nerve, MuSK provides instructions for building the neuromuscular synapse, including the attachment of motor nerve endings to muscle.

To test whether increasing attachment between nerve and muscle might keep synapses connected when they would otherwise be dismantled in ALS mice, the researchers used an antibody that stimulates MuSK to boost signaling from muscle to nerve. A single dose of a MuSK-stimulatory antibody, introduced into ALS mice after disease onset, increased the number of fully innervated neuromuscular synapses 2.6-fold.

Chronic dosing with the stimulatory antibody led to a sustained increase in the number of neuromuscular synapses for two months, and improved function of diaphragm muscle, which is critical for breathing. Untreated ALS mice survive for about five months, and the MuSK-stimulatory antibody prolonged their survival by about week.

"The therapeutic strategy described here targets a disease mechanism, namely the loss of neuromuscular synapses, which is common to familial and sporadic forms of ALS; and is based on a therapeutic antibody format with considerable clinical precedence," says Burden. "Although the MuSK agonist antibody cannot override the many pathological pathways that occur in motor neurons and in non-neuronal cells, therapeutic interventions that preserve neuromuscular synapses have the potential to improve the quality of life for a majority of ALS patients."
-end-
Along with Burden, the study was led by first author and Ph.D. 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 antibodies used in the study were provided by Genentech. The study was supported by grants from the National Institutes of Health (NIH) (R37 NS36193, RO1NS078375), the Robert Packard Center for ALS Research, and the ALS Association, along with funds from Above and Beyond, LLC, to Burden. Cantor was supported by an NIH training grant (T32 NS86750), and Mentis was also funded by the NIH (RO1 NS078375).

NYU Langone Health / NYU School of Medicine

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.