Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation
Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation
复制标题
DOI：
10.1111/j.1471-4159.2004.02726.x
复制
发表时间：
2004-10-01
影响因子：
4.7
通讯作者：
Hersch, SM
中科院分区：
文献类型：
--
作者：
Fox, JH;Barber, DS;Hersch, SM
胱胺是一种含二硫化物的小分子化学物质，在亨廷顿病（HD）的转基因小鼠和果蝇模型中具有神经保护作用，并在HD的体外模型中减少亨廷顿蛋白聚集体。胱胺在这些模型中的作用机制被广泛认为涉及在聚集体形成/稳定化过程中抑制转氨酶介导的突变亨廷顿蛋白的交联。在这项研究中，我们表明，胱胺，在体外和转基因小鼠模型的HD（R6/2），增加细胞抗氧化剂L-半胱氨酸的水平。几种氧化应激标志物在HD脑中增加。我们通过证明R6/2 HD脑中的代偿反应提供了小鼠HD中氧化应激的进一步证据。我们发现年龄依赖性增加前脑谷胱甘肽（GSH），并增加了参与GSH合成和解毒途径的蛋白质编码的转录水平，如定量PCR分析所示。考虑到氧化应激作为神经退行性变介质的普遍重要性，我们提出脑L-半胱氨酸水平的增加可能对HD具有保护作用。此外，胱胺对3-硝基丙酸诱导的小鼠纹状体损伤具有显着的保护作用。我们认为，胱胺在HD转基因小鼠中的神经保护作用是由多效性作用引起的，包括转谷氨酰胺酶抑制和抗氧化活性。
Cystamine, a small disulfide-containing chemical, is neuroprotective in a transgenic mouse and a Drosophila model of Huntington's disease (HD) and decreases huntingtin aggregates in an in vitro model of HD. The mechanism of action of cystamine in these models is widely thought to involve inhibition of transglutaminase mediated cross-linking of mutant huntingtin in the process of aggregate formation/stabilization. In this study we show that cystamine, both in vitro and in a transgenic mouse model of HD (R6/2), increases levels of the cellular antioxidant L-cysteine. Several oxidative stress markers increase in HD brain. We provide further evidence of oxidative stress in mouse HD by demonstrating compensatory responses in R6/2 HD brains. We found age-dependent increases in forebrain glutathione (GSH), and increased levels of transcripts coding for proteins involved in GSH synthesis and detoxification pathways, as revealed by quantitative PCR analysis. Given the general importance of oxidative stress as a mediator of neurodegeneration we propose that an increase in brain L-cysteine levels could be protective in HD. Furthermore, cystamine was dramatically protective against 3-nitropropionic acid-induced striatal injury in mice. We suggest that cystamine's neuroprotective effect in HD transgenic mice results from pleiotropic effects that include transglutaminase inhibition and antioxidant activity.