The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease.
The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease.
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DOI：
10.1111/j.1582-4934.2008.00543.x
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Bett JS;Benn CL;Ryu KY;Kopito RR;Bates GP
亨廷顿氏病（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白（htt）中的多聚谷氨酰胺束扩张引起。HD脑的特征在于存在泛素阳性神经元包涵体，这表明细胞泛素分布的紊乱可能有助于疾病病理学。事实上，几种神经退行性疾病是由遍在蛋白加工酶突变引起的，并且多聚遍在蛋白基因是抵抗细胞应激所必需的，这使得我们研究了扰乱泛在蛋白系统对HD的影响。我们将R6/2转基因HD小鼠与杂合多聚泛素Ubc敲除小鼠（Ubc+/−）杂交，并评估对R6/2神经学表型的影响。尽管R6/2表型在很大程度上不受影响，但令人惊讶的是，我们观察到与杂合Ubc敲除相关的各种行为活动的一些细微改善。有趣的是，免疫印迹分析显示，与基因抑制相关的单泛素化组蛋白H2 A（uH 2A）的水平在R6/2小鼠的大脑中显著增加。此外，R6/2; Ubc+/−小鼠中Ubc表达的减少在很大程度上阻止了uH 2A水平的增加。然而，我们无法通过使用有限数量的定量RT-PCR测定来显示R6/2-Ubc小鼠中uH 2A的量的变化对疾病相关的转录异常有影响。这些结果表明，聚集倾向的突变体htt的表达引起的泛素系统的干扰，这可能有助于疾病由于泛素的多样性和重要的作用。
Huntington’s disease (HD) is an inherited neurodegenerative disease caused by the expansion of a polyglutamine tract in the protein huntingtin (htt). HD brains are characterized by the presence of ubiquitin-positive neuronal inclusion bodies, suggesting that disturbances in the distribution of cellular ubiquitin may contribute to disease pathology. The fact that several neurodegenerative diseases are caused by mutations in ubiquitin-processing enzymes and that the polyubiquitin genes are required for resistance to cellular stress led us to investigate the effect of perturbing the ubiquitin system in HD. We crossed R6/2 transgenic HD mice with heterozygous polyubiquitin Ubc knockout mice (Ubc+/−) and assessed the effect on the R6/2 neurological phenotype. Although the R6/2 phenotype was largely unaffected, surprisingly we observed some subtle improvements in various behavioural activities correlating with heterozygous Ubc knockout. Interestingly, immunoblot analysis revealed that the levels of monoubiquitylated histone H2A (uH2A), a modification associated with gene repression, were significantly increased in the brains of R6/2 mice. Furthermore, the reduction of Ubc expression in R6/2; Ubc+/− mice largely prevented this increase in uH2A levels. However, we were not able to show by the use of a limited number of quantitative RT-PCR assays that changes in the amount of uH2A in the R6/2-Ubc mice had an effect on disease-associated transcriptional abnormalities. These results suggest that the expression of aggregation-prone mutant htt causes disturbances to the ubiquitin system, which may contribute to disease due to the diverse and important roles of ubiquitin.
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影响因子：
64.5
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
64.5
作者：
FINLEY, D;OZKAYNAK, E;VARSHAVSKY, A
通讯作者：
VARSHAVSKY, A
影响因子：
5.3
作者：
Baarends, WM;Wassenaar, E;Grootegoed, JA
通讯作者：
Grootegoed, JA
DOI：
10.1006/bbrc.2000.2568
发表时间：
2000-04-21
影响因子：
3.1
作者：
Kirschner, LS;Stratakis, CA
通讯作者：
Stratakis, CA
影响因子：
5.3
作者：
Kim, Mee-Ohk;Chawla, Prianka;Cha, Jang-Ho J.
通讯作者：
Cha, Jang-Ho J.