Structural Consequences of ALS-related Modifications of SOD1

描述(申请人提供)：编码铜/锌超氧化物歧化酶基因的至少119个突变与肌萎缩侧索硬化症有关。这些SOD1突变被认为会导致有毒性质，尽管这种有毒性质的性质尚未确定。在初步研究中，我们用氢/氢交换质谱仪比较了13种纯化的SOD1变异酶的动态性质，发现了一个共同的性质，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，包括天然和非天然的翻译后修饰，也干扰了SOD1的静电环，并将用氢/氢交换质谱仪验证这一假说。尽管增加静电环迁移率的生物学后果尚不完全清楚，但这一共同特性与SOD1突变通过聚集或异常结合其他细胞成分而产生毒性的假设是一致的。与公共卫生相关：包括肌萎缩侧索硬化症在内的神经退行性疾病已被证明非常难以治疗。这在一定程度上是因为研究人员不知道90%的肌萎缩侧索硬化症的病因。我们认为一种名为SOD1的蛋白质的聚集(粘连在一起)参与了ALS的进展，并将测试ALS中名为静电环的一段蛋白质是否受到破坏。

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.