But new research from the NYU School of Medicine has shedsome light on a possible method of slowing the muscular deterioration of ALS,granting those with the disease potential hope of retaining voluntary movementfor longer.
The new study, led by Dr. Steven J. Burden, a professor ofbiochemistry and molecular pharmacology and cell biology and a faculty memberof the Skirball Institute of Biomolecular Medicine at NYU School of Medicine,revolved around a protein known as muscle skeletal receptor tyrosine-proteinkinase (MuSK). By increasing the signaling activity of the enzyme in mousemodels of ALS, the researchers were able to keep nerve cells attached to musclelonger.
Since discovering the kinase in 1993, Burden's lab has beenworking to discover how the protein works and in what ways it can bemanipulated.
"MuSK's major function is in the formation andstabilization, or the maintenance, of nerve muscles synapses," says Burden,lead investigator for the study. "It's an enzyme, and it's expressed in themuscle, and it's important for the muscle to become specialized at the site wherethe nerve contacts the muscle. It's specialized in many, many, many ways, andany defects or deficiencies in the ability to become specialized there resultin the failure of the nerve to communicate with the muscle and stimulate musclecontraction. So it's really a very kind of master gene or master regulatoryenzyme involved in assembling or building the synapse."
It is not known what causes ALS, though Burden says thereare 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 foundin mitochondria, and the theory is that a mutation in the gene leads to adefect in mitochondria, which in turn leads to a poor energy supply in theaxon, or nerve terminal, which leads to a disconnection of the nerves from themuscle. Another theory is that mutations in the SOD1 gene cause improperfolding of proteins, leading to protein aggregation and healthy neuronsbecoming ill. Roughly 15 percent of all cases of ALS, Burden notes, aregenetic, while 85 percent are sporadic.
A third theory, which Burden says he and his colleaguestouch on in their paper, is that something happens to interrupt the delivery ofvital proteins to nerve terminals. Nerve terminals release acetylcholine, whichis necessary for proper function and muscle interaction, but the enzymes thatproduce it are made in the cell bodies, which for motor neurons are located inthe spinal cord. The idea, he explains, is that in cases of ALS, "this pathwayfor transporting proteins from cell body to nerve terminal becomes defective."
Burden and his colleagues hypothesized that by strengtheningthe signals that keep nerve terminals and muscles attached, they might be ableto delay denervation, or the loss of nerve contact, and preserve motor functionin the early stages of ALS. To test this, the researchers worked with mousemodels of the disease that were genetically predisposed to express MuSK atthree times the normal levels. As a result, the team was able to keep nervesattached to muscle for 30 to 40 days longer in the ALS mice with heightenedMuSK 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 representsapproximately 20 percent of the total lifespan of the mice in question. "If wewere to extrapolate these results to humans, you might expect a substantialimprovement in the quality of life for an ALS patient. This might mean that anALS patient would be able to eat, go to the bathroom, talk and breathe withoutassistance later into the disease. Importantly, therapeutic approaches toenhance this kind of retrograde signaling in a clinical setting can be readilyenvisaged."
The increased expression of MuSK did not prolong survival,as the nerve cells will still die, but it keeps nerve motor axons connected tomuscles longer.
"It is always exciting and gratifying when findings fromfundamental, basic science can be applied to treat disease," said Burden in astatement. "When we started, we discovered MuSK in fish and could onlyspeculate about its function. Then MuSK was found in other vertebrates,including mice and humans, and we learned that it is essential to form andmaintain neuromuscular synapses … It's very satisfying to study a molecule anda process in detail, to understand how a molecule works, how a synapse formsand then to apply this information in a disease setting."
Moving forward, Burden and his colleagues will try to answerseveral questions, such as what, if any, therapeutic options there might be toincrease expression of the enzyme. Genentech identified a few antibodies about15 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 tostimulate the kinase in muscle cells.
"For us that's the next important step," says Burden. "We'vebegun a collaboration with Genentech, and we're going to ask whether theseagonist antibodies that they studied in tissue culture function in vivo to stimulate the kinase, and ifthey do, if they're injected into a mouse that's a mouse model of ALS, willthey delay and decrease the extent of denervation and improve motor behavior."
The researchers will also try to determine if increasingMuSK expression in ALS mice after the onset of symptoms will be similarlyeffective.
"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 symptomsappear, as well as decrease the severity of the disease once symptoms have beenidentified."
