BROWN (US) — An important protein’s role in linking nerves and muscles may lead to treatments for conditions like Lou Gehrig’s disease.
In the absence of the protein biglycan, synapses at neuromuscular junctions in mice began to break up about five weeks after birth, according to a new study led by Brown University researchers and published in the Journal of Neuroscience.
Reintroducing biyglycan helped fix the loss of synaptic stability in cell culture.
The synaptic structures in mice lacking biglycan (bottom row) appear discontinuous compared to the synaptic structures in normal mice (top). (Credit: Fallon Lab, Brown University)
The research may be relevant to efforts to treat motor neuron diseases, such as amyotrophic lateral sclerosis (ALS, Lou Gehrig’s Disease) and spinal muscular atrophy.
“What neuromuscular junctions do second-by-second is essential for our brain to control movement and they are also important for the long-term health of both muscle and motor neurons,” says Justin Fallon, professor of neuroscience and the paper’s senior author.
“A treatment that sustains or supports the synapse could promote the health of motor neurons and muscle.”
In previous work, Fallon, a member of the Brown Institute for Brain Science, has shown that in mice with the same genetic mutation as Duchenne patients, biglycan promotes the activity of another natural protein, utrophin, that can significantly reduce the muscle degradation that patients suffer. Utrophin essentially takes over for dystrophin, which is the protein Duchenne patients cannot produce.
Now Fallon’s research group has found another important role for biglycan. In the new multi-institutional study, lead author Alison Amenta and a team of other scientists found that biglycan binds and helps activate and target a receptor enzyme called MuSK, which works like a foreman or master regulator over other proteins that build and stabilize the neuromuscular junction.
Mice engineered to lack biglycan developed normal junctions at first, but by five weeks after birth their synapses became much more likely to break into fragmented shadows of their former selves. In experiments the scientists saw that up to 80 percent of synapses in biglycan-lacking mice were unstable.
Biglycan-lacking mice also showed other structural defects including misaligned neurotransmitter receptors and extra folds near synapses.
“We think it is most likely that these folds are remnants of previous synaptic sites,” that have since withered, the authors write in the paper.
Amenta, Fallon, and their team also found that in mice lacking biglycan, levels of MuSK at neuromuscular junction synapses were reduced by a factor of more than ten. In another experiment, they found that recombinant biglycan could rescue the stability of synaptic structures in model cell culture system.
Relevance to motor neuron diseases
The findings help set the stage for testing biglycan as a potential therapy in animal models of motor neuron disease, Fallon says.
“As an extracellular protein that can be delivered systemically that acts to stabilize the neuromuscular junction, we propose that biglycan could be a protein therapeutic for motor neuron diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis, or ALS,” Fallon says.
In addition to Fallon and Amenta, additional investigators contributed to the findings from Brown, as well as the University of Miami, the Medical College of Georgia, Lifecell Corp., the University of Houston, and the National Institute of Dental and Craniofacial Research.
In 2010, Brown licensed Fallon’s biglycan intellectual property to the Providence startup company Tivorsan Pharmaceuticals, which is working toward human trials of biglycan and has received funding from the Muscular Dystrophy Association.
The National Institutes of Health and the Muscular Dystrophy Association funded the research.
More news from Brown University: http://news.brown.edu/