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Scientists Show Cell Environment is Important in ALS

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www.ProHealth.com • October 3, 2003


The neighborhood matters: Packard Center scientists show cell environment is important in ALS

In amyotrophic lateral sclerosis (ALS), neighborhood may be everything, if a new study in mouse models of the disease holds true for patients.

ALS, or Lou Gehrig's disease, brings about a gradual death of the motor neurons that activate muscles. Paralysis follows. But according to work described today in the journal Science, the cells that are next to motor neurons -- but aren't themselves nerve cells -- can play a major role in advancing or limiting the disease.

"What we've been given is a new principle for extending survival or, perhaps, overcoming ALS, based on how many healthy cells surround an ailing motor nerve cell," says Don Cleveland, Ph.D., a scientist with The Packard Center for ALS Research at Johns Hopkins and, with Larry Goldstein, Ph.D., co-leader of the research team. "All this has great implications for stem cell therapy," he adds. "We now believe delivery of normal, non-neuronal cells to spinal cords could be completely protective, even without replacement of a single motor neuron."

In a series of experiments, the team measured the effect of having different proportions of healthy cells to at-risk cells in mice, clocking their survival time. Normally, the scientists work with standard animal models of ALS. Those mice or rats carry a mutant human gene -- called SOD1 -- that triggers a rare, inherited form of the disease in people. In these models, every cell carries a mutant SOD1 gene. The animals typically slip into death by the time they're six to eight months of age.

But in this study, the researchers used chimeric animals -- mice engineered to be a mix of normal cells, also called wild type, and cells containing the mutant SOD1 gene. They tagged the cells with molecular flags to make it clear which were which. The percent of wild-type cells in the animals' spinal cords ranged from 5 to 90 percent.

Having wild type cells mixed in had the effect of extending mouse survival from one to eight months, depending on the number of cells and type of SOD1 mutation. In a second group of chimeric mice, brought about by a different technique and with a different type of tracer, the animals survived disease-free until sacrificed for study at an age at least twice the age at which typical SOD1 animal models die.

Even though further study showed that as high as three-fourths of the motor neurons in the animals' spinal cords carried the mutant gene, all the motor neurons remained amazingly healthy, apparently from having healthy non-neuronal cells in the neighborhood. This was especially true of the second batch of mice, which had no microscopic evidence of disease.

"It's really striking," says Cleveland, "to see what a small number of normal cells effectively eliminated damage to motor neurons from the ALS-causing genetic error."

The opposite effect also appeared: mice with normal motor neurons but with surrounding cells carrying an SOD1 mutation showed early signs of disease. Normal neurons, then, can apparently acquire something toxic from at-risk non-neuronal neighboring cells.

"So we're seeing a real-life metaphor here," says Cleveland. "Living in a bad environment can damage good cells. And more important, restoring a better environment to 'bad' neurons by surrounding them with healthy neighbors can significantly lessen toxic effects. In some cases, having normal cells completely stops motor neuron death."

Research conducted by Center scientist and team member Jean-Pierre Julien, Ph.D., at Laval University in Quebec was a key contribution to the results. Researchers Cleveland and Goldstein are both at the University of California, San Diego, where Cleveland heads the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research.

The research was funded by the Packard Center for ALS Research at Johns Hopkins, Project ALS, The ALS Association, the U.S. National Institutes of Health, the Canadian Institutes of Health Research, The Angel Fund for ALS Research and the U.S. Veterans Administration.

Headquartered in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a collaboration of scientists worldwide who are working aggressively to develop new treatments and a cure for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The Center is the only institution of its kind dedicated solely to the disease. Its research is meant to translate from the laboratory bench to the clinic in record time.



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