Bethesda, MD -- A new study indicates that mutant Cu/Znsuperoxide dismutase (SOD1) enzymes that are associated with aninherited form of Lou Gehrig's disease cause the protein to becomesticky in tissues. Partial unfolding of the mutant protein can exposehydrophobic residues that may promote abnormal interactions with otherproteins or membranes in the cell.
The research appears as the "Paper of the Week" in the August 19issue of the Journal of Biological Chemistry, an American Society forBiochemistry and Molecular Biology journal.
Over 5,600 people in the U.S. are diagnosed with amyotrophiclateral sclerosis (ALS) or Lou Gehrig's disease each year. About 30,000Americans have the disease at any given time, and 10% of cases areinherited.
"Amyotrophic lateral sclerosis is a neurodegenerative disorderin which neurons of the motor pathways in the brain and spinal corddie," explains Dr. Lawrence J. Hayward of the University ofMassachusetts Medical School. "It typically strikes during middle age,and although it may start with only mild weakness, the symptoms canspread insidiously over months to impair mobility, speech andswallowing, and ultimately the muscles required for respiration."
Despite the prevalence of ALS, the biological mechanisms thatkill the motor neurons in most patients are incompletely understood.However, for a fraction of inherited ALS patients, mutations in thegene for SOD1 cause the disease by creating a toxic enzyme. Evidencesuggests that misfolding or partial unfolding of mutant SOD1 proteinsin these patients might be key to the toxicity.
Hoping to learn more about how SOD1 contributes to ALS, Dr.Hayward began to study the properties of several ALS-causing SOD1mutants in research sponsored by the National Institutes of Health andthe ALS Association.
"Our efforts have focused upon trying to explain how over 100different mutant forms of SOD1 cause inherited ALS," says Dr. Hayward."The initial results were puzzling because some mutations had dramaticeffects on copper and zinc binding, enzymatic activity, and stabilityof the protein, but many other mutations seemed to cause only subtlechanges in these properties in vitro. Yet all of the mutants were knownto be toxic in patients."
As a result of several additional experiments done in his laband by other groups, Dr. Hayward suspected that the mutant proteinsmight be more vulnerable than the normal enzyme to specific stresses intissues. In their Journal of Biological Chemistry paper, Dr. Haywardand his colleagues at the University of Massachusetts Medical Schoolshow that when the mutant SOD1 enzymes are exposed to reagents that candisrupt some of the protein's bonds or remove its metal ions, theybecome much stickier than the normal protein.
"The mutants, but not the normal SOD1, adhere to a hydrophobicor 'greasy' surface, and this property could promote abnormalinteractions with other proteins or membranes in the cell," explainsDr. Hayward. "How well different tissues can handle this burden ofsticky protein, especially during aging, may be one factor thatdetermines which cell types are most vulnerable in the disease. It wasinteresting to us that the adherent forms were not restricted to thenervous system in the mouse models but were also seen in other tissuessuch as heart and skeletal muscle. It is possible that this propertycould contribute to abnormalities in muscle, while other tissues suchas kidney do not accumulate hydrophobic SOD1 despite a high expressionlevel of the mutants."
These results may lead to new treatments for some forms of ALS.For example, if researchers can minimize the hydrophobic exposure orcan understand how certain tissues prevent build-up of the sticky formsof SOD1, they might be able to boost defenses in tissues known to besusceptible to mutant SOD1 accumulation.
The Journal of Biological Chemistry's Papers of the Week is anonline feature which highlights the top one percent of papers receivedby the journal. Brief summaries of the papers and explanations of whythey were selected for this honor can be accessed directly from thehome page of the Journal of Biological Chemistry online at www.jbc.org.
The American Society for Biochemistry and Molecular Biology(ASBMB) is a nonprofit scientific and educational organization withover 11,000 members in the United States and internationally. Mostmembers teach and conduct research at colleges and universities. Othersconduct research in various government laboratories, nonprofit researchinstitutions, and industry.
Founded in 1906, the Society is based in Bethesda, Maryland, onthe campus of the Federation of American Societies for ExperimentalBiology. The Society's primary purpose is to advance the sciences ofbiochemistry and molecular biology through its publications, theJournal of Biological Chemistry, The Journal of Lipid Research,Molecular and Cellular Proteomics, and Biochemistry and MolecularBiology Education, and the holding of scientific meetings.
For more information about ASBMB, see the Society's website at www.asbmb.org.
The above story is based on materials provided by American Society for Biochemistry and Molecular Biology. Note: Materials may be edited for content and length.
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