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New Insights Into Muscle-Specific Kinase Could Impact Myasthenia Gravis, Other Diseases

Article

The new research could help identify ways to preserve neuromuscular junctions.

Muscle-specific kinase (MuSK) is essential to the development of functional neuromuscular junctions, but scientists have yet to fully understand its activation and downstream signaling.

In a new review article in Cellular Signalling, study investigators explain newly uncovered insights into MuSK and how those breakthroughs might help treat MuSK-related disorders.

The authors noted that MuSK is notable among receptor tyrosine kinases because its activation and signaling are “particularly tightly controlled” and that MuSK activity requires a multistep interaction process.

When MuSK’s activity is impaired, it results in severe muscle weakness. Such is the case in myasthenia gravis (MG), an autoimmune disease in which autoantibodies target MuSK and/or other important molecules related to the neuromuscular junction. Most patients with MG have antibodies that target the acetylcholine receptor, although about 5% to 8% of people with MG have MuSK-positive cases. Previous research suggests such cases are often more severe than other types of the disease.

The present authors said treating and understanding MuSK-positive MG has been challenging, but that investigation into the condition and its pathology has been ongoing. In one study, for instance, researchers found that MuSK-MG patients had a shift in circulating T follicular helper cells and an increased ratio of those cells to T follicular regulator cells. T follicular helper cells support B cells and high-affinity antibody production.

“Interleukin [IL]-17 and IL-21 production in MuSK-MG CD4+ T cells was augmented, as well as the generation of immunoglobulin G molecules pointing to Tfh17 reactivity as significant contributor to B-cell activation and autoantibody production in MuSK-MG patients,” they wrote.

The authors added that rituximab (Rituxan), the most effective MG treatment, targets B cells, although it is unclear if it affects T follicular helper reactivity.

After outlining the latest research regarding MuSK signaling, they turned to potential therapeutic development opportunities, noting that motor neuron diseases—which are incurable and can be fatal—are often preceded by the loss of functional neuromuscular junctions. They said a recent study of patients who have motor neuron disease showed that the morphology of the neuromuscular junctions in patients’ muscle biopsies was “severely disturbed.”

Some researchers have probed whether there might be a means to preserve neuromuscular junctions as a therapeutic strategy to prevent the loss of motor function and thereby benefit patients with motor neuron diseases.

A decade ago, a study in a mouse model of amyotrophic lateral sclerosis (ALS) suggested that an overexpression of MuSK could reduce the extent of denervation and lead to improved motor function, but the present investigators noted that it did not affect overall survival.

“This hypothesis was confirmed in a similar investigation using adenovirus-mediated expression of human DOK7 in an ALS mouse model,” they wrote. “The authors observed an increase in MuSK activation, a suppression of nerve terminal denervation, and a containment of muscle atrophy, ultimately enhancing motor activity and life span of ALS mice.”

However, a separate study found different results, and the authors said the causes for these different outcomes are not yet clarified.

If agonist MuSK antibodies can be a therapeutic strategy for diseases like ALS, the current consensus is that they would be one part of the solution, since they would not have an impact on the underlying cause of ALS, the authors noted. The same might be true for the treatment of spinal muscular atrophy, they noted, since current therapies for that disease often do not alleviate the neuromuscular symptoms of the disease.

Reference

Prömer J, Barresi C, Herbst R. From phosphorylation to phenotype - recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK. Cell Signal. 2023;104:110584. doi:10.1016/j.cellsig.2022.110584

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