Structural Consequences of ALS-related Modifications of SOD1

描述（由申请人提供）：至少119个编码Cu/Zn超氧化物歧化酶的基因突变与肌萎缩性侧索硬化症有关。这些SOD1突变被认为会导致毒性，尽管这种毒性的性质尚未确定。在初步研究中，我们使用氢/氘交换质谱法比较了13种纯化的SOD1变异酶的动态特性，发现了一个共同的特性，即影响SOD1静电环的结构和动态变化。我们假设SOD1的其他修饰，包括原生和非原生翻译后修饰，也会扰乱SOD1静电环，并将使用氢/氘交换质谱法验证这一假设。虽然静电环迁移率增加的生物学后果尚不完全清楚，但这一共同特性将与SOD1突变通过与其他细胞成分的聚集或异常关联而发挥毒性的假设相一致。公共卫生相关性：神经退行性疾病，包括肌萎缩侧索硬化症，已被证明非常难以治疗。这部分是由于研究人员不知道90%的ALS的病因。我们提出一种名为SOD1的蛋白质的聚集（粘在一起）参与了ALS的进展，并将测试称为静电环的蛋白质部分是否在ALS中受损。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.