The disease starts slow. It begins with minor missteps, small errors typing. But within a matter of only a few years, those small mistakes, falls and fumbles progress to complete paralysis. The muscles that keep you breathing stop doing their job, leading to lethal respiratory failure. And the whole time, cognition remains intact, rendering you keenly aware of what is happening, helpless to improve the condition.
Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease or ALS, is a devastating, rapidly advancing disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. But researchers at NYU School of Medicine have identified a new target for slowing the deterioration of physical function for which the disease is so well known.
In their new study, published August 30, 2012 online ahead of print in Cell Reports, lead investigator Steven J. Burden, PhD, and colleagues show that, by increasing the signaling activity of a protein called muscle, skeletal receptor tyrosine-protein kinase (MuSK), they were able to keep nerve cells attached to muscle longer into the progression of the disease in a mouse model of ALS.
Approximately one out of every 1,000 people will develop ALS in their lifetime and only two and a half to three years separate diagnosis and death on average. Currently, the only treatments available for ALS are therapies designed to bring a patient some comfort while the body increasingly fails to respond to intent, but there are no therapies available for slowing the progression of the disease.
The withdrawal, or detachment, of motor nerve terminals from muscle is the first sign of disease in all forms of ALS, followed by the death of nerve cells, or neurons. When the terminals detach, the muscles are denervated, or disconnected from the nerve, leaving the neurons no longer able to send messages to muscles, and the ability of the brain to initiate and control muscle movement is lost.
Vast research efforts have focused on ways to keep the neurons from dying, but the death of nerve cells occurs after the separation of nerve and muscle and, once separated, motor neurons are no longer able to send messages to muscles telling them to contract, regardless of whether the neurons are dead or alive. Dr. Burden and his co-researchers theorized that strengthening the signals that normally keep nerve terminals and muscle attached might delay denervation and preserve motor function during the early phases of disease progression, improving the quality of life for patient and family.
By tripling the expression of MuSK in a mouse model of ALS, the researchers were able to keep nerves attached to muscle, preserving motor function, for 30 to 40 days longer than in ALS mice that did not receive the increase in MuSK.
"This is a substantial amount of time for the ALS mouse," Dr. Burden said, explaining that 30 to 40 days is about 20 percent of the total lifespan of these mice. "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 increase in MuSK expression did not prolong survival of ALS mice, Dr. Burden explained. Despite the increased expression, nerve cells will still ultimately die, but the increase in MuSK signaling from the muscle keeps the nerve motor axons connected to muscle for a longer time, and this connection is essential for signals from the brain to be received by the muscle.
"The neuromuscular synapse is the only synapse in the body that is required for survival," said Dr. 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. "Defects at other synapses alter your perception of the world, but you survive. The neuromuscular synapse is required not only to move, but also to breathe and live."
Dr. Burden's lab discovered MuSK in 1993 and has been focused on revealing how the protein works and whether its activity can be manipulated to affect disease in the years since. The current study was conducted in mice born with increased MuSK expression and later developed neuromuscular ALS symptoms. Dr. Burden and colleagues will next investigate whether increasing MuSK activity in ALS mice after symptoms arise, to resemble the mid-life onset of symptoms in humans, will likewise be effective at maintaining neuromuscular synapses. In this regard, they will look for molecules that can stimulate MuSK to increase the activity, or function of the kinase, with hopes that drugs may be formulated for this task. Long-term, Dr. Burden and his team hope to utilize such drugs to learn whether they can slow, halt or reverse the disease once it has begun progressing.
"It is always exciting and gratifying when findings from fundamental, basic science can be applied to treat disease," Dr. Burden said. "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 and that myasthenia gravis, an auto-immune disease, can be caused by auto-antibodies to MuSK. 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. We don't have all the answers and we don't know with absolute certainty that our approach will work in humans, but we're confident that we're headed in the right direction. Fortunately, we have a mouse model of ALS that replicates the human disease, so we are hopeful that increasing MuSK activity in ALS patients will likewise preserve attachment of nerve terminals and improve motor function."
- María J. Pérez-García, Steven J. Burden. Increasing MuSK Activity Delays Denervation and Improves Motor Function in ALS Mice. Cell Reports, 2012; DOI: 10.1016/j.celrep.2012.08.004
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