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THE NEIGHBORHOOD MATTERS: PACKARD CENTER
SCIENTISTS SHOW CELL ENVIRONMENT'S IMPORTANT IN ALS 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 neighbor motor neurons-that 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-"calico" 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 five 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. 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. ______________
This work is typical of the strong collaborative approach that marks
the Packard Center. 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. |
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