Global changes to the ubiquitin system in Huntington's disease
Global changes to the ubiquitin system in Huntington's disease
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DOI：
10.1038/nature06022
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发表时间：
2007-08-09
期刊：
影响因子：
64.8
通讯作者：
Kopito, Ron R.
中科院分区：
文献类型：
--
作者：
Bennett, Eric J.;Shaler, Thomas A.;Kopito, Ron R.
亨廷顿氏病（HD）是一种显性遗传的神经退行性疾病，由亨廷顿蛋白（HTT）基因（也称为HD） CAG三重重复扩增引起，其特征是受影响神经元中聚积了聚谷氨酰胺扩增的HTT蛋白片段（1,2）。HD包涵体异常富集泛素是HD和许多其他神经退行性疾病（包括阿尔茨海默病和帕金森病）的诊断特征（3,4），这表明泛素代谢功能障碍可能与这些疾病的发病机制有关（5,6）。由于多泛素链修饰的蛋白质调节了许多基本的细胞过程，包括蛋白质降解、细胞周期、转录、DNA修复和膜运输(7)，泛素信号的中断可能对神经元功能和存活产生广泛的影响。尽管在HD8-11和其他神经退行性疾病的细胞培养模型中，泛素依赖性蛋白降解受损（12,13），但在HD患者或该疾病的动物模型中，尚无法评估泛素-蛋白酶体系统（UPS）的功能，并且UPS损伤在神经退行性疾病发病机制中的功能作用仍存在争议（14-16）。在这里，我们利用一种基于质谱的方法来量化多泛素链（17），并证明这些链的丰度是UPS功能的忠实内源性生物标志物。从R6/2转基因HD小鼠模型、HD敲入模型和人类HD患者中发现，Lys 48连接的多泛素链在发病早期在大脑中积累，证实UPS功能障碍是HD病理的一致特征。Lys 63-和Lys 11-连接的多泛素链，通常与蛋白酶体靶向无关，也在R6/2小鼠大脑中积累。因此，HD与泛素系统的全球变化的联系比以前认识到的要大得多。
Huntington's disease (HD) is a dominantly inherited neuro-degenerative disorder caused by expansion of CAG triplet repeats in the huntingtin (HTT) gene (also called HD) and characterized by accumulation of aggregated fragments of polyglutamine-expanded HTT protein in affected neurons(1,2). Abnormal enrichment of HD inclusion bodies with ubiquitin, a diagnostic characteristic of HD and many other neurodegenerative disorders including Alzheimer's and Parkinson's diseases(3,4), has suggested that dysfunction in ubiquitin metabolism may contribute to the pathogenesis of these diseases(5,6). Because modification of proteins with polyubiquitin chains regulates many essential cellular processes including protein degradation, cell cycle, transcription, DNA repair and membrane trafficking(7), disrupted ubiquitin signalling is likely to have broad consequences for neuronal function and survival. Although ubiquitin-dependent protein degradation is impaired in cell-culture models of HD8-11 and of other neurodegenerative diseases(12,13), it has not been possible to evaluate the function of the ubiquitin-proteasome system (UPS) in HD patients or in animal models of the disease, and a functional role for UPS impairment in neurodegenerative disease pathogenesis remains controversial(14-16). Here we exploit a mass-spectrometry-based method to quantify polyubiquitin chains(17) and demonstrate that the abundance of these chains is a faithful endogenous biomarker of UPS function. Lys 48-linked polyubiquitin chains accumulate early in pathogenesis in brains from the R6/2 transgenic mouse model of HD, from a knock-in model of HD and from human HD patients, establishing that UPS dysfunction is a consistent feature of HD pathology. Lys 63- and Lys 11-linked polyubiquitin chains, which are not typically associated with proteasomal targeting, also accumulate in the R6/2 mouse brain. Thus, HD is linked to global changes in the ubiquitin system to a much greater extent than previously recognized.