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WHEN THE CHAPERONE'S NOT AROUND Most ALS scientists dream that what causes the disease would turn out to be something dramatic that they'd just overlooked: an odd, neurotoxic chemical that comes from exposure to pesticides after eating walnuts, for example. But researchers at The Packard Center are realizing that finding the disease's cause--and the cure--will instead depend on small, quiet detective work at the molecular level. Recently, Center scientist Val Culotta has made a discovery typical of that approach. While it won't make the front page of major dailies, it's an important find because it further clarifies the biology of a process that goes awry in ALS. Not only does her work save her fellow scientists months of research time, but it also suggests more finely-targeted studies to reveal what goes wrong. And when you've got 24 investigators pooling such discoveries, that whittles the problem down. Val Culotta, like other ALS researchers, is aware that in both the common,
sporadic form of ALS and the familial sort, patients' motor neurons show
an unnatural clumping of abnormally-structured protein. The clumps can
be made up of a protein, SOD1. "Scientists generally agree that this
clumping, or aggregation, might play havoc with motor neurons. It could
trigger the symptoms of the disease and cell death," says How, she asks, do you cause the protein misfolding that leads to aggregates? From her studies of SOD1, which is an enzyme, Culotta well understands its structure and behavior. She typically observes SOD1 within the confines of single-celled yeasts, her test laboratory. Culotta studies both natural yeast SOD1 and human SOD1 that yeasts have been prodded into manufacturing. In order to function normally, SOD1 requires zinc and copper, she says. Recently, Culotta has focused on the enzyme's relation to the latter metal. How does SOD1 get its copper? Typically, the metal, which doesn't float around randomly in cells, is instead captured by a "chaperone" molecule which efficiently hands it over to the enzyme. For some time, scientists thought ALS might be caused by a malfunction in the chaperones and their delivery of copper. But Packard Center researcher Phil Wong and colleagues showed that ALS model mice engineered to be without the chaperones still came down with motor neuron disease. "It was elegant work," says Culotta. "But it also raised another question." Even though Wong's test mice lacked copper chaperones and even though those molecules were needed to "complete" SOD1 enzymes, the researchers saw that the mouse cells still had a fair amount of complete, active SOD1. Culotta reasoned there must be another way, a non-chaperone way, to deliver copper to the enzyme. So she tried every other molecule she could think of with a role in supplying copper in a living cell. Finally, Culotta found two molecules: glutathione and the enzyme, glutathione reductase. "When we eliminated those two molecules in cells, the activity of SOD1 enzymes dropped dramatically," she says. That showed they're very likely part of an alternate route animal cells use to supply copper. "Finding that," she says, "took an enormous amount of time." But Culotta's study has led to an interesting find. In cultures of cells
that lack copper chaperones but which, instead, seem to rely upon the
glutathione molecules for their copper, those cells have far less SOD1.
"It's very preliminary," she says, "but there's a suggestion
that these alternate routes may be highly damaging to SOD1. Damage could
lead to aggregation." Culotta hopes to begin studies soon to see
how this fits into the ALS process. |
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