Widespread protein aggregation as an inherent part of aging in C. elegans.
Widespread protein aggregation as an inherent part of aging in C. elegans.
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DOI：
10.1371/journal.pbio.1000450
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发表时间：
2010-08-10
期刊：
影响因子：
9.8
通讯作者：
Kenyon C
中科院分区：
文献类型：
--
作者：
David DC;Ollikainen N;Trinidad JC;Cary MP;Burlingame AL;Kenyon C
秀丽隐杆线虫中有数百种蛋白质由于衰老而变得不溶并易于聚集。这些数据表明，这些蛋白质影响疾病相关的蛋白质聚集和毒性。异常的蛋白质聚集是许多与年龄相关的疾病的标志，但很少有人知道蛋白质是否在非疾病环境中随着年龄的增长而聚集。使用系统的蛋白质组学方法，我们确定了数百种蛋白质，随着年龄的增长变得更加不溶性的多细胞生物秀丽隐杆线虫。预测这些蛋白质显著富集在β-折叠中，其促进疾病蛋白质聚集。引人注目的是，这些不溶性蛋白质在人类神经变性中发现的聚集体中高度过量。我们在体内研究了这些蛋白质中的几种，并证实了它们随着年龄的增长而聚集的倾向。不同的蛋白质聚集在不同的组织和细胞区室中。胰岛素/IGF-1信号传导的减少显著延迟甚至停止了蛋白质的不溶性和聚集，这也减缓了衰老。我们发现了一个显着的蛋白质之间的重叠，成为不溶性和蛋白质，影响寿命和/或聚谷氨酰胺重复聚集。此外，过度表达一个聚集蛋白增强多聚谷氨酰胺重复病理。总之，我们的研究结果表明，广泛的蛋白质不溶性和聚集是衰老的固有部分，它可能会影响寿命和神经退行性疾病。在神经退行性疾病中，如阿尔茨海默氏病和亨廷顿氏病，特定的蛋白质逃离细胞的质量控制系统并结合在一起，形成不溶性的聚集体。到目前为止，人们对蛋白质是否在非疾病情况下聚集知之甚少。在这项研究中，我们发现，在没有疾病的情况下，衰老过程本身导致线虫中数百种蛋白质的不溶解和聚集倾向增加。这些易于聚集的蛋白质具有不同的结构和功能特性。我们询问这种固有的年龄依赖性蛋白质聚集是否会影响神经退行性疾病。我们发现，与那些聚集在老蠕虫中的蛋白质类似的蛋白质也被确定为人类疾病聚集体的次要成分。此外，我们发现，较高水平的固有蛋白质聚集加剧了C。elegans亨廷顿病模型。固有蛋白质聚集是一种新的衰老生物标志物。了解如何调节它将导致对衰老和蛋白质聚集疾病的机制的重要见解。
Several hundred proteins become insoluble and aggregation-prone as a consequence of aging in Caenorhabditis elegans. The data indicate that these proteins influence disease-related protein aggregation and toxicity. Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in β-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease. In neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, specific proteins escape the cell's quality-control system and associate together, forming insoluble aggregates. Until now, little was known about whether proteins aggregate in a non-disease context. In this study, we discovered that the aging process itself, in the absence of disease, leads to the insolubilization and increased aggregation propensity of several hundred proteins in the roundworm Caenorhabditis elegans. These aggregation-prone proteins have distinct structural and functional proprieties. We asked if this inherent age-dependent protein aggregation impacts neurodegenerative diseases. We found that proteins similar to those aggregating in old worms have also been identified as minor components of human disease aggregates. In addition, we showed that higher levels of inherent protein aggregation aggravated toxicity in a C. elegans Huntington's disease model. Inherent protein aggregation is a new biomarker of aging. Understanding how to modulate it will lead to important insights into the mechanisms that underlie aging and protein aggregation diseases.
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影响因子：
3.7
作者：
Basso M;Samengo G;Nardo G;Massignan T;D'Alessandro G;Tartari S;Cantoni L;Marino M;Cheroni C;De Biasi S;Giordana MT;Strong MJ;Estevez AG;Salmona M;Bendotti C;Bonetto V
通讯作者：
Bonetto V
DOI：
10.1073/pnas.96.7.3590
发表时间：
1999-03-30
影响因子：
11.1
作者：
Chiti, F;Webster, P;Dobson, CM
通讯作者：
Dobson, CM
影响因子：
9.2
作者：
Copeland, Jeffrey M.;Cho, Jaehyoung;Walker, David W.
通讯作者：
Walker, David W.
影响因子：
13.3
作者：
Florez-McClure, Maria L.;Hohsfield, Lindsay A.;Link, Christopher D.
通讯作者：
Link, Christopher D.
影响因子：
4.8
作者：
Cuervo, AM;Dice, JF
通讯作者：
Dice, JF