Sticky mutant proteins implicated in Lou Gehrig...( initial results were puzzling because ...)

initial results were puzzling because some mutations had dramatic effects on copper and zinc binding, enzymatic activity, and stability of the protein, but many other mutations seemed to cause only subtle changes in these properties in vitro. Yet all of the mutants were known to be toxic in patients."

As a result of several additional experiments done in his lab and by other groups, Dr. Hayward suspected that the mutant proteins might be more vulnerable than the normal enzyme to specific stresses in tissues. In their Journal of Biological Chemistry paper, Dr. Hayward and his colleagues at the University of Massachusetts Medical School show that when the mutant SOD1 enzymes are exposed to reagents that can disrupt some of the protein's bonds or remove its metal ions, they become much stickier than the normal protein.

"The mutants, but not the normal SOD1, adhere to a hydrophobic or 'greasy' surface, and this property could promote abnormal interactions with other proteins or membranes in the cell," explains Dr. Hayward. "How well different tissues can handle this burden of sticky protein, especially during aging, may be one factor that determines which cell types are most vulnerable in the disease. It was interesting to us that the adherent forms were not restricted to the nervous system in the mouse models but were also seen in other tissues such as heart and skeletal muscle. It is possible that this property could contribute to abnormalities in muscle, while other tissues such as kidney do not accumulate hydrophobic SOD1 despite a high expression level of the mutants."

These results may lead to new treatments for some forms of ALS. For example, if researchers can minimize the hydrophobic exposure or can understand how certain tissues prevent build-up of the sticky forms of SOD1, they might be able to boost defenses in tissues known to be susceptible to mutant SOD1 accumulation.

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Contact: Nicole Kresge
nkresge@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology
10-Aug-2005

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