'Back at square one' to find culprit in fa...( After almost 10 years of research with ...)

'Back at square one' to find culprit in familial ALS

After almost 10 years of research with cells and animals to learn what makes a certain enzyme act as a "bad guy" in the progressive and fatal disease amyotrophic lateral sclerosis (ALS), Johns Hopkins scientists report that a leading candidate -- copper -- is off the hook.

In mice that develop ALS-like paralysis because of a malfunctioning enzyme called superoxide dismutase (SOD1), the researchers found that taking away copper had no effect on the pace of the disease, even though it is normally required for the enzyme's activity. The results appear in the current Advanced Online Publication section of Nature Neuroscience.

"Since the 1993 discovery of the enzyme's involvement in ALS, it's been proposed that copper might be to blame," explains Philip Wong, Ph.D., associate professor of pathology and neuroscience. "However, the long and short of it is that preventing copper from getting to SOD1 didn't make any difference in the onset of disease or survival of these ALS mice."

Because free copper is deadly to cells, the metal is carried to and fro by proteins called chaperones. A few years ago, researchers from Hopkins and elsewhere discovered the chaperone that delivers copper to SOD1 and named it CCS. In the new study, postdoctoral fellow Jamuna Subramaniam crossed mutant-SOD1 mice, which develop ALS-like symptoms, and mice that lack CCS to see how things changed if copper couldn't get to the enzyme.

The research team also tested other potential influences on symptoms, such as changes in the amounts of SOD1 present, and did experiments to see if copper was sneaking through to SOD1 by a back door. The sum of their results shows that copper and CCS play no role in the disease in these mice, says Wong.

"This was a direct test, in animals, of the copper hypothesis in SOD1-associated ALS, so we're sort of back to square one to examine other possible pathways," he says.

Not only did the disease pathway not change, but just
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
12-Mar-2002

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