Towards Solving the Mystery of Lou Gehrig's Disease

Filed in archive Genomics, Proteomics and Bioinformatics on July 1, 2007

An important mystery about a protein that plays a key role in Lou Gehrig's disease - a progressive, fatal neurodegenerative disorder that strikes without warning - may have already been solved by Chemists from UCLA and the University of Florence in Italy.

The said protein -- copper-zinc superoxide dismutase - was only implicated to ALS in 1993.

Lou Gehrig's disease is a form of ALS (amyotrophic lateral sclerosis).

Copper-zinc superoxide dismutase, which was discovered in the 1960s, is an antioxidant enzyme that protects cells from free radicals, unstable atoms or molecules that can cause cell damage.
The link with ALS came when researchers sequenced the genes of people who have the inherited form of ALS and found that some of them have mutations in the gene that codes for this enzyme.
While the inherited form represents only a fraction of all ALS cases, this marked the first time there was any indication of a cause for any form of ALS.

According to Joan Selverstone Valentine, UCLA professor of chemistry and biochemistry and a member of UCLA's molecular biology Institute who has been studying this particular protein since the 1970s:

"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. 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"".

Valentine's laboratory has made more than two dozen mutant, ALS-causing enzymes (since copper-zinc superoxide dismutase have been linked to ALS) to try to understand their properties and what makes them toxic.

Together with colleagues from the University of Florence, Valentine's team think they know what makes the protein toxic: because it may not be there at all. These hypotheses have been backed by research findings reported in an article appearing in the July 3 print edition of the Proceedings of the National Academy of Sciences (currently online).

Valentine further explained:

"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.

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 treatment.

This research is the result of a long, successful international collaboration between UCLA and the University of Florence. Our colleagues in Italy are exceptional scientists."

The research team is now testing the said hypotheses.

Find more details from the full report.

[In Photo: The structure of one subunit of copper-zinc superoxide dismutase. The orange and blue spheres represent copper and zinc ions, which bind to the protein and stabilize it. UCLA and Italian chemists believe the toxic form of the protein lacks these metal ions. Credit: UCLA]