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 UCLA–University 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.
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 forms of the protein that would have different inorganic properties,” she said. “We were making mutant forms of this enzyme to study, but with no connection to disease.
“I remember the day in March 1993 that the announcement came — it was on the front page of The New York Times — that ALS has been linked to superoxide dismutase (SOD), but the article didn’t say which superoxide dismutase; I was hoping it was our enzyme. It took me all day to track down the scientists to find out which SOD it actually was. It was our SOD. It was a very exciting day.”
“When we made the mutant proteins, each one seemed to be totally different,” she said. “Some of the mutant proteins that cause the disease are identical to the normal protein in every property we measure.”
Valentine and Bertini have known each other since she was a graduate student and he was a research associate at Princeton University. Initially, they were both inorganic chemists who did not intend to do biological research. They have just published an authoritative new textbook called “Biological Inorganic Chemistry: Structure and Reactivity,” with co-authors Harry Gray at the California Institute of Technology and the late Edward Stiefel from Princeton University. The textbook is designed for both undergraduate and graduate students.
“All of us who work in the field hope our research will lead to a treatment of ALS,” Valentine said. “What we really want is to diagnose and prevent ALS before its onset. We’re still a long way from that, but we’re making progress.”
Stuart Wolpert | EurekAlert!
Researchers target protein that protects bacteria's DNA 'recipes'
21.08.2018 | University of Rochester
Protein interaction helps Yersinia cause disease
21.08.2018 | Schwedischer Forschungsrat - The Swedish Research Council
There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.
The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
21.08.2018 | Ecology, The Environment and Conservation
21.08.2018 | Life Sciences
21.08.2018 | Power and Electrical Engineering