May 12, 2003
HOUSTON, TX - Understanding what makes certain motor neurons vulnerable to degeneration while others are resistant, may provide critical information for the development of future Amyotrophic Lateral Sclerosis (ALS) treatments.
ALS, or Lou Gehrig's disease, involves the progressive breakdown of motor neurons, the nerve cells that control muscular activity. It results in severe muscle weakness and difficulty in speaking, swallowing, and breathing. Average survival after diagnosis is two to three years.
In most ALS patients, the predominant damage occurs to the lower motor neurons.
"Any time you want to make a motion, twitch a muscle, do any kind of action, you have to activate the lower motor neurons," said Dr. Dennis Mosier, a staff neurologist at the Houston VA Medical Center (HVAMC). Mosier is focusing on understanding what kills these neurons.
"The neurons controlling the face, tongue, and limb muscles are quite sensitive to degeneration, yet the eye motor neurons are extremely resistant," said Mosier, also an assistant professor of neurology at Baylor College of Medicine. "The disparity is so dramatic. If we could give all motor neurons that kind of resistance, we could probably extend life in patients with the disease by years."
One obvious difference is that the resistant, or surviving, motor neurons produce higher levels of calcium-binding proteins. These proteins control calcium levels within the cell.
"Studies of motor neurons of ALS patients reveal an overloading of calcium, which could cause motor neuron injury," Mosier said.
Using mice known to develop an ALS-like syndrome, he is evaluating whether increased production of calcium-binding proteins slows down disease progression. When ALS mice were bred with mice that overproduce the calcium-binding protein parvalbumin, Mosier found that the offspring appeared to develop the ALS-like disease at a slower rate.
To maximize the benefit, Mosier is examining how different levels of calcium-binding protein impact the disease and whether calcium-binding proteins in combination with other treatments provide an even greater effect.
"While calcium overload in the motor neurons is a possible trigger for degeneration, these levels cannot be impacted by changes in calcium intake," Mosier said. "So, people currently taking calcium supplements have no need to worry or alter their intake."
Mosier's laboratory at the HVAMC is also examining the role of immune-inflammatory mechanisms in the development of ALS. In additional mouse studies, the researchers are stimulating immune cells to see if they alter motor neuron function and calcium handling.
"If the data gained in our laboratory studies is strong, we would next approach pharmaceutical companies who have drugs that can alter calcium handling. If a drug appears to be effective, it could ultimately advance to clinical trials," Mosier said.
Mosier is already engaged in clinical trials looking at ways to inhibit the function of various immune cells that may play a role in ALS.
Ultimately, Mosier hopes the work will lead to additional methods of treating ALS. Only one medication, riluzole, has FDA approval for treatment of ALS. It extends survival by an average of two to three months.
"Different parts of the motor neuron appear to respond differently to interventions and may have to be treated in different ways," Mosier said.
The neuron's cell body resides in the central nervous system, but the axon, which transmits the impulses to muscle, extends to the far reaches of the body, where it resides in a different environment and is exposed to different stresses.
"Cells residing near motor neurons may also play protective or injurious roles. To successfully treat motor neuron disease, we will have to find ways to target the various components of the system," he said.
Mosier believes effective treatment will involve a combination of therapies due to this complex nature of motor neurons and their supporting cells.
Supported with more than $18 million annually, research conducted by HVAMC staff ensures veterans access to cutting-edge medical and health care technology. The HVAMC Research & Development (R&D) Program is an integral part of the medical center's mission. The production of new knowledge, techniques, and products has led to improved prevention, diagnosis, treatment, and control of disease, as well as correction of or compensation for, defects.
article by Katherine Hoffman, HVAMC Research and Development
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Point of Contact: VHAHOU Public Affairs04/21/04 08:25