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 Gehrig's 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, Valentine's 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 UCLA's 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 protein's 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 journal's 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 treatment, she said.
The research team is testing the hypothesis. Valentine, who was elected to the National Academy of Sciences in 2005 and to the American Academy of Arts and Sciences this year, praised her colleagues.This research is the result of a long, successful international collaboration between UCLA and the University of Florence, she said.Our colleagues in Italy are exceptional scientists.
Co-authors on the Proceedings of the National Academy of Sciences research are Lucia Banci, a professor of chemistry at the University of Florence who is affiliated with the FiorGen Foundation; Armando Durazo, a UCLA graduate student of chemistry and biochemistry; Stefania Girotto, a postdoctoral scholar at the University of Florence; Edith Butler Gralla, a senior research chemist at UCLA; Manuele Martinelli and Miguela Vieru, graduate students at the University of Florence; and Julian P. Whitelegge, an adjunct professor at the Semel Institute for Neuroscience and Human Behavior at UCLA and UCLA's Brain Research Institute.
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, Valentine said.
For many years, Valentine's laboratory has studied the normal version of the protein. While the normal protein has copper and zinc, scientists can make it with no metals. When it is first made inside the cell, it has no metals and only acquires them later, Valentine said.
We studied what happens to the protein if you have the metals, if you have no metals and if you have part of the metals, she said.
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 Alzheimer's and Parkinson's 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.