Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease.
Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease.
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DOI：
10.1093/hmg/ddp260
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发表时间：
2009-09-01
影响因子：
3.5
通讯作者：
Andersen PM
中科院分区：
文献类型：
--
作者：
Prudencio M;Hart PJ;Borchelt DR;Andersen PM
到目前为止，已在家族性肌萎缩侧索硬化症(ALS)患者中发现了146种不同的超氧化物歧化酶1(SOD1)突变。遗传SOD1突变的患者的平均发病年龄为45-47岁。然而，尽管病程长短差异很大，但也有与特定突变相关的一致病程的例子(例如，A4V，少于2年)。在本研究中，我们使用了来自SOD1相关ALS家系的大量数据来确定30多个不同突变型SOD1的疾病特征与生化/生物物理特性之间的相关性。使用可靠的细胞培养实验，我们证明了所有与肌萎缩侧索硬化症相关的SOD1突变都增加了蛋白质的固有聚集倾向。然而，在不同的突变体中，这样做的相对倾向有很大的差异。我们不能用已知蛋白质性质的差异来解释聚集率的变化，如酶活性、蛋白质热稳定性、突变位置或蛋白质电荷的变化程度。同样，我们不能用这些特性来解释SOD1相关的ALS家系中病程的变异性。然而，我们发现，大多数患者表现出可重复的较短病程的家系与突变有关，这些突变显示出诱导SOD1聚集的高固有倾向。
To date, 146 different mutations in superoxide dismutase 1 (SOD1) have been identified in patients with familial amyotrophic lateral sclerosis (ALS). The mean age of disease onset in patients inheriting mutations in SOD1 is 45–47 years of age. However, although the length of disease duration is highly variable, there are examples of consistent disease durations associated with specific mutations (e. g. A4V, less than 2 years). In the present study, we have used a large set of data from SOD1-associated ALS pedigrees to identify correlations between disease features and biochemical/biophysical properties of more than 30 different variants of mutant SOD1. Using a reliable cell culture assay, we show that all ALS-associated mutations in SOD1 increase the inherent aggregation propensity of the protein. However, the relative propensity to do so varied considerably among mutants. We were not able to explain the variation in aggregation rates by differences in known protein properties such as enzyme activity, protein thermostability, mutation position or degree of change in protein charge. Similarly, we were not able to explain variability in the duration of disease in SOD1-associated ALS pedigrees by these properties. However, we find that the majority of pedigrees in which patients exhibit reproducibly short disease durations are associated with mutations that show a high inherent propensity to induce aggregation of SOD1.
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影响因子：
14.5
作者：
Jonsson, PA;Graffmo, KS;Marklund, SL
通讯作者：
Marklund, SL
DOI：
10.1073/pnas.212527999
发表时间：
2002-12-10
影响因子：
11.1
作者：
Chiti, F;Calamai, M;Dobson, CM
通讯作者：
Dobson, CM
DOI：
10.1097/01.jnen.0000248545.36046.3c
发表时间：
2006-12-01
影响因子：
3.2
作者：
Jonsson, P. Andreas;Graffmo, Karin S.;Marklund, Stefan L.
通讯作者：
Marklund, Stefan L.
在遗传背景中的蛋白质多态性不稳定突变SOD1毒性的直接表型表达。
影响因子：
4.5
作者：
Gidalevitz T;Krupinski T;Garcia S;Morimoto RI
通讯作者：
Morimoto RI
影响因子：
3.8
作者：
Gong, B.;Lim, M. C. Y.;Morton, A. J.
通讯作者：
Morton, A. J.