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UCLA, Italian chemists move closer to solving Lou Gehrig's disease mystery

Chemists from UCLA and the University of Florence in Italy may have solved an important mystery about a protein that plays a key role in a particular form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease, a progressive, fatal neurodegenerative disorder that strikes without warning.

Joan Selverstone Valentine, UCLA professor of chemistry and biochemistry, has studied the protein copper-zinc superoxide dismutase since the 1970s, long before it was implicated in ALS in 1993. Since the link was discovered, Valentines laboratory has made more than two dozen mutant, ALS-causing enzymes, most of which have only one wrong amino acid out of 153, to try to understand their properties and learn what makes them toxic.

Some of the mutant proteins are very different from the normal protein, but others are virtually identical to the normal protein yet they all cause the disease, said Valentine, a member of UCLAs Molecular Biology Institute. That was the real mystery. You wrack your brain: What is similar among all these proteins" They seem so different. How can they all cause the same disease"

Now Valentine and her colleagues, including Ivano Bertini, professor of chemistry at the University of Florence and director of the European Magnetic Resonance Center, think they know. In ALS patients, the proteins copper and zinc may not be there at all. They present evidence for this hypothesis in new research published in Proceedings of the National Academy of Sciences, currently online and available in the journals July 3 print edition.

If we keep the metals entirely out of the protein, we can explain the toxicity, since even the normal protein forms aggregate at physiological conditions when the metals are gone, Valentine said. It was such a puzzle, but this hypothesis can solve it.

If scientists can figure out why ALS patients lack the copper and zinc, that would be a major advance that could lead to trea
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Contact: Stuart Wolpert
swolpert@support.ucla.edu
310-206-0511
University of California - Los Angeles
27-Jun-2007


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