A study published Feb. 14 in the Journal of Neuroscience shows that the protein biglycan plays an important role in stabilizing synapses, or communication sites, between nerves and muscles. These findings may have clinical implications for patients with degenerative muscular diseases.
The paper supports the idea that biglycan activates muscle-specific kinase, MuSK, an enzyme that coordinates the stabilization of the neuromuscular junction, said Professor of Medical Science Justin Fallon, one of the study's authors.
When biglycan is absent, the neuromuscular junction, which is shaped like a pretzel, fragments, Fallon said. The unstable synapse then draws back toward the axon, impeding communication between nerves and muscles.
"That synaptic command (by biglycan) is essential for the health of the neuron and the cell," said Fallon. "Without it, you are paralyzed."
To see what happened without biglycan, researchers used a "knockout process" to genetically engineer mice that did not produce the protein, said Marian Young, a researcher at the National Institute of Dental and Craniofacial Research.
In the biglycan-free mice, researchers saw evidence of synaptic withdrawal. Fallon said the presence of biglycan, by activating the expression of MuSK, maintains structural stability and prevents this synaptic withdrawal from occurring.
The protein also serves other important functions in the body and has possible roles in healing fractures and strengthening bones, Young said, adding that she plans to study this for her next research project. Biglycan is also found in cartilage, and deficiencies of the protein can lead to premature osteoporosis.
Because it exists on the outside of cells, biglycan has proven to be a good candidate for protein therapy for degenerative muscular diseases, Fallon said. Released in the bloodstream, biglycan could correct muscular degeneration and synaptic instability in patients, improving muscle function in patients with Duchenne muscular dystrophy or Lou Gehrig's disease, also called amyotrophic lateral sclerosis.
Fallon's lab is looking to start clinical trials of biglycan therapy on humans in the near future. The Muscular Dystrophy Association recently awarded a $1 million grant to Fallon's company, Tivorsan Pharmaceuticals, according to the company's website.
"The good news is that much of the progress we've made with (Duchenne muscular dystrophy) therapy could be applied to ALS," Fallon said. "We wouldn't have to start from scratch if it were to show promise."
Rita Balice-Gordon, professor of neuroscience at the Perelman School of Medicine at the University of Pennsylvania, said the team's study might eventually lead to new therapies for neuromuscular diseases. "It's possible that synapse dysfunction could be ameliorated and that this would result in preservation of nerve-muscle function," she wrote in an email to The Herald.
The next question Fallon wants to answer is whether increased synaptic stability through biglycan could help patients with diseases where the synapse itself dies. The team also plans to investigate if biglycan could prolong the overall life of motor neurons.