SOD1-associated ALS: a promising system for elucidating the origin of protein-misfolding disease
SOD1-associated ALS: a promising system for elucidating the origin of protein-misfolding disease
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DOI：
10.2976/1.2995726
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Oliveberg, Mikael
中科院分区：
文献类型：
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作者：
Nordlund, Anna;Oliveberg, Mikael
肌萎缩侧索硬化症（ALS）是一种与同二聚体酶超氧化物歧化酶（SOD 1）的错误折叠和聚集有关的神经退行性疾病。与其他神经退行性疾病的前体相比，SOD 1是一种可溶性且易于研究的具有免疫球蛋白样结构的蛋白质。此外，有超过120个ALS引起的SOD 1突变可供在分子水平上详细阐明疾病触发因素。在这篇文章中，我们回顾了最近的进展，在表征的折叠和组装途径的SOD 1二聚体，这是如何受到ALS激发突变。尽管这些突变的性质不同，但到目前为止，结果提供了一个令人惊讶的简单性。ALS引发突变降低蛋白质稳定性或净排斥电荷：由非天然蛋白质缔合引发的疾病机制的经典标志。此外，突变体数据确定了未成熟的SOD 1单体作为细胞毒性途径出现的物种，并指出受损的折叠协同性作为关键的疾病决定因素。这些数据的获得相对容易，使得SOD 1成为一个有前途的模型，用于阐明其他神经退行性疾病的起源，其中前体蛋白在结构上更难以捉摸。[DOI：10.2976/1.2995726]
Amyotropic lateral sclerosis (ALS) is a neurodegenerative disease linked to misfolding and aggregation of the homodimeric enzyme superoxide dismutase (SOD1). In contrast to the precursors of other neurodegenerative diseases, SOD1 is a soluble and simple-to-study protein with immunoglobulin-like structure. Also, there are more than 120 ALS-provoking SOD1 mutations at the disposal for detailed elucidation of the disease-triggering factors at molecular level. In this article, we review recent progress in the characterization of the folding and assembly pathway of the SOD1 dimer and how this is affected by ALS-provoking mutations. Despite the diverse nature of these mutations, the results offer so far a surprising simplicity. The ALS-provoking mutations decrease either protein stability or net repulsive charge: the classical hallmarks for a disease mechanism triggered by association of non-native protein. In addition, the mutant data identifies immature SOD1 monomers as the species from which the cytotoxic pathway emerges, and point at compromised folding cooperativity as a key disease determinant. The relative ease by which these data can be obtained makes SOD1 a promising model for elucidating also the origin of other neurodegenerative diseases where the precursor proteins are structurally more elusive. [DOI: 10.2976/1.2995726]