At least 119 mutations in the gene encoding Cu/Zn superoxide dismutase are associated with amyotrophic lateral sclerosis. These SOD1 mutations are believed to result in a toxic property, although the nature of this toxic property has not been identified. In preliminary studies we compared the dynamic properties of thirteen purified SOD1 variant enzymes using hydrogen/deuterium exchange mass spectrometry and identified a shared property, namely structural and dynamic change affecting the electrostatic loop of SOD1. We hypothesize that other modifications of SOD1, including native and non-native post-translational modifications, also perturb the SOD1 electrostatic loop and will test this hypothesis using hydrogen/deuterium exchange mass spectrometry. Although the biological consequences of increased electrostatic loop mobility are not fully understood, this common property would be consistent with hypotheses that SOD1 mutations exert toxicity via aggregation or aberrant association with other cellular constituents.
The neurodegenerative diseases, including ALS, have proven extraordinarily difficult to treat. This is due in part to the fact that researchers do not know the cause of >90% of ALS. We propose that the aggregation (sticking together) of a protein named SOD1 is involved in ALS progression, and will test if a section of the protein called the electrostatic loop is damaged in ALS.
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