Structural Consequences of ALS-related Modifications of SOD1

描述（由申请人提供）：编码Cu/Zn超氧化物歧化酶的基因中至少有119个突变与肌萎缩侧索硬化症相关。这些SOD 1突变被认为导致毒性，尽管这种毒性的性质尚未确定。在初步研究中，我们比较了13个纯化的SOD 1变体酶的动态特性，使用氢/氘交换质谱，并确定了一个共同的属性，即结构和动态变化影响静电环的SOD 1。我们假设，其他修饰的SOD 1，包括本地和非本地的翻译后修饰，也扰乱了SOD 1的静电环，并将测试这一假设使用氢/氘交换质谱。虽然静电环迁移率增加的生物学后果尚未完全了解，但这种共同性质与SOD 1突变通过与其他细胞成分聚集或异常缔合而产生毒性的假设一致。公共卫生相关性：神经退行性疾病，包括ALS，已经被证明是非常难以治疗的。这部分是由于研究人员不知道>90%的ALS的原因。我们提出，一种名为SOD 1的蛋白质的聚集（粘在一起）与ALS的进展有关，并将测试这种蛋白质的一部分（称为静电环）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.