Moving closer to solving Lou Gehrig's disease mystery, UCLA, Italian chemists 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 neuro-degenerative 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," he added.
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.
"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," Valentine said
"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.
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.
"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 neuro-degenerative 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 t
han 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," she added..
Valentine and Bertini 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. 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," Valentine said.
The study is published in Proceedings of the National Academy of Sciences, which is currently online and available in the journal's July 3 print edition. Related medicine news :1
. Fizzy Logic For A Perfect Drink: Courtesy Boffins2
. Boffins Identify Fifth Gene Behind Joubert Syndrome3
. Boffins Find Link Between Common Sleep Disorder and Hypertension4
. Boffins Identify Molecule That Might Treat Food Allergy5
. Boffins Identify Gene That Helps Regulates Body Weight6
. Boffins Link Atkins Diet With Bowel Cancer7
. Boffins Develop New Technique to Hunt Illness-causing Mutants in Non-gene DNA8
. A Closer Look into Vitamin D and Fractures9
. Scientists Closer To Identifying Gene Connected To Alzheimers10
. Scientist Move A Step Closer To Treating Genetic Obesity11
. Chlamydia Vaccine a Step Closer to Reality