EVENTS | VIEW CALENDAR
MuSK musters hope for ALS treatment
NEW YORK—Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, remains one of the most devastating degenerative muscular diseases. In those with the disease, motor nerve terminals withdraw from muscle, detaching muscles from nerves and leading to the death of nerve cells. When the neurons can no longer communicate with muscles a person's brain can no longer initiate muscle control, and voluntary movement is lost. The disease advances rapidly to the point of complete paralysis in a few years, with roughly two and a half years between diagnosis and death. There is no cure, and the current therapies are largely palliative, meant to bring comfort while remaining unable to halt the progressive loss of muscle control.
But new research from the NYU School of Medicine has shed some light on a possible method of slowing the muscular deterioration of ALS, granting those with the disease potential hope of retaining voluntary movement for longer.
The new study, led by Dr. Steven J. Burden, a professor of biochemistry and molecular pharmacology and cell biology and a faculty member of the Skirball Institute of Biomolecular Medicine at NYU School of Medicine, revolved around a protein known as muscle skeletal receptor tyrosine-protein kinase (MuSK). By increasing the signaling activity of the enzyme in mouse models of ALS, the researchers were able to keep nerve cells attached to muscle longer.
Since discovering the kinase in 1993, Burden's lab has been working to discover how the protein works and in what ways it can be manipulated.
"MuSK's major function is in the formation and stabilization, or the maintenance, of nerve muscles synapses," says Burden, lead investigator for the study. "It's an enzyme, and it's expressed in the muscle, and it's important for the muscle to become specialized at the site where the nerve contacts the muscle. It's specialized in many, many, many ways, and any defects or deficiencies in the ability to become specialized there result in the failure of the nerve to communicate with the muscle and stimulate muscle contraction. So it's really a very kind of master gene or master regulatory enzyme involved in assembling or building the synapse."
It is not known what causes ALS, though Burden says there are several ideas. One thought, he says, is a mutation in a gene known as SOD1, "the first genetic mutation shown to cause ALS." This enzyme is usually found in mitochondria, and the theory is that a mutation in the gene leads to a defect in mitochondria, which in turn leads to a poor energy supply in the axon, or nerve terminal, which leads to a disconnection of the nerves from the muscle. Another theory is that mutations in the SOD1 gene cause improper folding of proteins, leading to protein aggregation and healthy neurons becoming ill. Roughly 15 percent of all cases of ALS, Burden notes, are genetic, while 85 percent are sporadic.
A third theory, which Burden says he and his colleagues touch on in their paper, is that something happens to interrupt the delivery of vital proteins to nerve terminals. Nerve terminals release acetylcholine, which is necessary for proper function and muscle interaction, but the enzymes that produce it are made in the cell bodies, which for motor neurons are located in the spinal cord. The idea, he explains, is that in cases of ALS, "this pathway for transporting proteins from cell body to nerve terminal becomes defective."
Burden and his colleagues hypothesized that by strengthening the signals that keep nerve terminals and muscles attached, they might be able to delay denervation, or the loss of nerve contact, and preserve motor function in the early stages of ALS. To test this, the researchers worked with mouse models of the disease that were genetically predisposed to express MuSK at three times the normal levels. As a result, the team was able to keep nerves attached to muscle for 30 to 40 days longer in the ALS mice with heightened MuSK expression than in those with normal levels of MuSK expression.
"This is a substantial amount of time for the ALS mouse, " said Burden in a press release, noting that 30 to 40 days represents approximately 20 percent of the total lifespan of the mice in question. "If we were to extrapolate these results to humans, you might expect a substantial improvement in the quality of life for an ALS patient. This might mean that an ALS patient would be able to eat, go to the bathroom, talk and breathe without assistance later into the disease. Importantly, therapeutic approaches to enhance this kind of retrograde signaling in a clinical setting can be readily envisaged."
The increased expression of MuSK did not prolong survival, as the nerve cells will still die, but it keeps nerve motor axons connected to muscles longer.
"It is always exciting and gratifying when findings from fundamental, basic science can be applied to treat disease," said Burden in a statement. "When we started, we discovered MuSK in fish and could only speculate about its function. Then MuSK was found in other vertebrates, including mice and humans, and we learned that it is essential to form and maintain neuromuscular synapses … It's very satisfying to study a molecule and a process in detail, to understand how a molecule works, how a synapse forms and then to apply this information in a disease setting."
Moving forward, Burden and his colleagues will try to answer several questions, such as what, if any, therapeutic options there might be to increase expression of the enzyme. Genentech identified a few antibodies about 15 years ago that bound to MuSK and mimicked what occurs in vivo and could serve as agonists for the enzyme, stimulating it, Burden says. When tested in a tissue culture dish, the antibodies were shown to stimulate the kinase in muscle cells.
"For us that's the next important step," says Burden. "We've begun a collaboration with Genentech, and we're going to ask whether these agonist antibodies that they studied in tissue culture function in vivo to stimulate the kinase, and if they do, if they're injected into a mouse that's a mouse model of ALS, will they delay and decrease the extent of denervation and improve motor behavior. "
The researchers will also try to determine if increasing MuSK expression in ALS mice after the onset of symptoms will be similarly effective.
"We haven't given up hope that MuSK might do both," he adds, "that it might delay, decrease the severity of the disease before any symptoms appear, as well as decrease the severity of the disease once symptoms have been identified."