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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro
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Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro

机译：与肌萎缩性侧索硬化症相关的铜/锌超氧化物歧化酶突变体在体外显示出增强的聚集体形成

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摘要

Mutations in Cu/Zn superoxide dismutase (SOD) are associated with the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). There is considerable evidence that mutant SOD has a gain of toxic function; however, the mechanism of this toxicity is not known. We report here that purified SOD forms aggregates in vitro under destabilizing solution conditions by a process involving a transition from small amorphous species to fibrils. The assembly process and the tinctorial and structural properties of the in vitro aggregates resemble those for aggregates observed in vivo. Furthermore, the familial ALS SOD mutations A4V, G93A, G93R, and E100G decrease protein stability, which correlates with an increase in the propensity of the mutants to form aggregates. These mutations also increase the rate of protein unfolding. Our results suggest three possible mechanisms for the increase in aggregation: (i) an increase in the equilibrium population of unfolded or of partially unfolded states, (h) an increase in the rate of unfolding, and (iii) a decrease in the rate of folding. Our data support the hypothesis that the gain of toxic function for many different familial ALS-associated mutant SODs is a consequence of protein destabilization, which leads to an increase in the formation of cytotoxic protein aggregates. [References: 39]
机译：铜/锌超氧化物歧化酶（SOD）中的突变与致命性神经退行性疾病肌萎缩性侧索硬化症（ALS）相关。有大量证据表明，突变型SOD具有毒性功能。但是，这种毒性的机理尚不清楚。我们在这里报告说，纯化的SOD在体外不稳定溶液条件下通过涉及从小的无定形物质到原纤维的过渡过程形成聚集体。体外聚集体的组装过程以及着色和结构性质类似于体内观察到的聚集体。此外，家族性ALS SOD突变A4V，G93A，G93R和E100G降低了蛋白质稳定性，这与突变体形成聚集体的倾向增加相关。这些突变也增加了蛋白质展开的速率。我们的结果提出了三种可能的聚集增加机制：（i）未折叠或部分未折叠状态的平衡种群增加，（h）展开速度增加，以及（iii）折叠速度降低折叠。我们的数据支持以下假设：许多不同的家族性ALS相关突变SOD获得毒性功能是蛋白质不稳定的结果，这导致细胞毒性蛋白质聚集物形成的增加。 [参考：39]

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