The research of the UCLAUniversity of Florence team has indicated it is the metal-free protein that is likely to be toxic. The protein misfolds when the copper and zinc are not present, but folds properly when they are there.
Before copper and zinc are inserted, the protein can misfold under physiological conditions, Valentine said.
There is evidence that ALS is associated with this misfolding of the protein, which becomes toxic in some way that is not known and has properties similar to misfolded proteins associated with other neurodegenerative disorders like Alzheimers and Parkinsons diseases, Valentine said.
Is there a way to slow down this process to give the cell more time to eliminate the misfolded proteins in all of these diseases" Would a strategy to reduce or prevent protein misfolding work against these and other diseases" These are avenues for further investigation by researchers.
When Valentine first began working on copper-zinc superoxide dismutase, she was not a biochemist but a biological inorganic chemist and hardly knew what ALS was. She was interested in the enzyme, which is unique in that it has copper and zinc so close together.
Her laboratory isolated and characterized the enzyme, but Valentine was less interested in its biological properties than in the inorganic chemistry. She was more interested, for example, in how the protein influenced the reactivity of the copper or zinc, or how the copper and zinc influenced the structure of the enzyme. She and her colleagues were among the pioneers in taking the copper and zinc out and putting other metals in to see what would happen. Her laboratory put more emphasis on biological factors over time.
When I moved to UCLA in 1980, we started working on copper-zinc superoxide dismutase in yeast, a model organism, using the then new tools of molecular biology to redesign the protein and make new mutant
Contact: Stuart Wolpert
University of California - Los Angeles