Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.
Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.
复制标题
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。
DOI：
10.1371/journal.pgen.1000399
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
Morimoto RI
中科院分区：
文献类型：
--
作者：
Gidalevitz T;Krupinski T;Garcia S;Morimoto RI
遗传背景对构象疾病中易聚集蛋白的毒性具有很强的调节作用。除了影响突变蛋白的错误折叠和聚集行为外，假定修饰基因的多态性可能影响导致疾病表型的分子过程。家族性肌萎缩性侧索硬化症（ALS）病例亚组中的SOD 1突变赋予显性但临床可变的毒性，被认为是由突变SOD 1蛋白的错误折叠和聚集介导的。虽然毒性机制仍然未知，但SOD 1突变的性质及其表达的遗传背景似乎都很重要。为了解决这个问题，我们建立了一个秀丽隐杆线虫模型，系统地研究聚集行为和遗传相互作用的突变形式的SOD 1。三种结构不同的SOD 1突变体在C. elegans肌细胞导致聚集体的异质群体的出现，并且仅与轻度的细胞功能障碍有关。然而，引入不稳定的温度敏感性突变到遗传背景中强烈增强了SOD 1突变体的毒性，导致在允许条件下以依赖于特定SOD 1突变的方式暴露几种有害表型。观察到的表型的性质是依赖于温度敏感性突变的存在，而其突变率反映了温度敏感性和SOD 1突变的特定组合。因此，构象疾病的特定毒性表型可能不是简单地由于致病突变蛋白的错误折叠/聚集毒性，而是可能通过它们与含有轻度不稳定错义等位基因的细胞途径的遗传相互作用来定义。正确的折叠和稳定性对蛋白质功能至关重要。在细胞中，分子伴侣和降解酶的网络促进折叠，防止聚集并确保错误折叠的蛋白质的降解，从而维持蛋白质稳态。在许多疾病中，包括肌萎缩性侧索硬化症（ALS），错误折叠和聚集的单个突变蛋白的表达引起强烈依赖于遗传背景的细胞毒性。为了解决遗传背景对聚集倾向蛋白毒性的影响，我们建立了一个C。超氧化物歧化酶1（SOD 1）的几种不同ALS相关突变体的错误折叠和聚集的elegans模型。在一个野生型遗传背景（N2），这些蛋白质仅表现出轻微的细胞毒性，尽管强大的，特异性的聚集表型。然而，当SOD 1突变体在轻度不稳定的蛋白质多态性的背景下表达时，它们的毒性增强，并且暴露出许多不同的表型。这些合成表型反映了失稳定的多态性蛋白的功能丧失。此外，这些表型中的每一种的暴露程度取决于SOD 1突变的性质。这些数据表明，在遗传背景中存在轻度不稳定的多态性可能会调节和指导蛋白质聚集疾病的特定毒性表型。
Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles. Correct folding and stability are essential for protein function. In cells, a network of molecular chaperones and degradative enzymes facilitate folding, prevent aggregation and ensure degradation of the misfolded proteins, thus maintaining protein homeostasis. In many diseases, including Amyotrophic Lateral Sclerosis (ALS), expression of a single mutant protein that misfolds and aggregates causes cellular toxicity that is strongly dependent on the genetic background. To address the influence of genetic background on the toxicity of aggregation-prone proteins, we established a C. elegans model of misfolding and aggregation of several distinct ALS-related mutants of superoxide dismutase 1 (SOD1). In one wild type genetic background (N2), these proteins exhibited only mild cellular toxicity despite strong, mutant-specific aggregation phenotypes. However, when SOD1 mutants were expressed in the background of mildly destabilized protein polymorphisms, their toxicity was enhanced and a number of distinct phenotypes were exposed. These synthetic phenotypes reflected the loss-of-function of the destabilized polymorphic proteins. Furthermore, the degree to which each of these phenotypes was exposed depended on the nature of the SOD1 mutation. These data suggest that the presence of mildly destabilizing polymorphisms in the genetic background may modulate and direct the specific toxic phenotypes in protein aggregation diseases.
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