Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

02.07.2007
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.

... more about:
»Mutant »UCLA »copper »dismutase »inorganic »misfold »superoxide »zinc

“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!
Further information:
http://www.ucla.edu

Further reports about: Mutant UCLA copper dismutase inorganic misfold superoxide zinc

More articles from Life Sciences:

nachricht New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences

nachricht The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Previous evidence of water on mars now identified as grainflows

21.11.2017 | Physics and Astronomy

NASA's James Webb Space Telescope completes final cryogenic testing

21.11.2017 | Physics and Astronomy

New catalyst controls activation of a carbon-hydrogen bond

21.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>