hMTH1 expression protects mitochondria from Huntington's disease-like impairment.
hMTH1 expression protects mitochondria from Huntington's disease-like impairment.
复制标题
DOI：
10.1016/j.nbd.2012.09.002
复制
发表时间：
2013-01
影响因子：
6.1
通讯作者：
Bignami M
中科院分区：
文献类型：
--
作者：
Ventura I;Russo MT;De Nuccio C;De Luca G;Degan P;Bernardo A;Visentin S;Minghetti L;Bignami M
亨廷顿病（Huntington disease，HD）是由亨廷顿蛋白（Huntingtin，Htt）基因CAG重复序列扩增引起的神经退行性疾病。hMTH 1（降解氧化嘌呤核苷三磷酸的人类水解酶）的表达在化学HD小鼠模型中赠款保护，其中HD样特征由线粒体毒素3-硝基丙酸（3-NP）诱导。为了进一步研究氧化dNTPs和HD样神经变性之间的关系，我们研究了HD遗传细胞模型中hMTH 1表达的影响，例如表达突变htt（HdhQ 111）的纹状体细胞。hMTH 1的表达保护这些细胞免受3-NP和H2 O2诱导的杀伤，通过抵消突变体HT依赖性增加的脆弱性和核和线粒体DNA 8-羟基鸟嘌呤水平的积累。hMTH 1的表达逆转了HdhQ 111细胞线粒体膜电位的降低，并延迟了与3-NP处理相关的线粒体活性氧的增加。hMTH 1介导的线粒体保护作用的进一步迹象是3-NP诱导的线粒体形态改变的部分逆转和DRP 1和MFN 1蛋白的调节，其控制线粒体的融合/分裂速率。最后，与体外研究结果一致，在3-NP体内治疗后，转基因hMTH 1表达小鼠的心脏、肌肉和脑线粒体DNA中的8-羟基鸟嘌呤水平显著低于野生型动物。HMTH 1在突变型HT表达纹状体细胞中提供针对细胞死亡的防御HMTH 1在突变型HT表达纹状体细胞中改善线粒体功能HMTH 1在体内保护线粒体免受内源性和3-NP诱导的氧化
Huntington disease (HD) is a neurodegenerative disease caused by expansion of CAG repeats in the huntingtin (Htt) gene. The expression of hMTH1, the human hydrolase that degrades oxidized purine nucleoside triphosphates, grants protection in a chemical HD mouse model in which HD-like features are induced by the mitochondrial toxin 3-nitropropionic acid (3-NP). To further examine the relationship between oxidized dNTPs and HD-like neurodegeneration, we studied the effects of hMTH1 expression in a genetic cellular model for HD, such as striatal cells expressing mutant htt (HdhQ111). hMTH1 expression protected these cells from 3-NP and H2O2-induced killing, by counteracting the mutant htt-dependent increased vulnerability and accumulation of nuclear and mitochondrial DNA 8-hydroxyguanine levels. hMTH1 expression reverted the decreased mitochondrial membrane potential characteristic of HdhQ111 cells and delayed the increase in mitochondrial reactive oxygen species associated with 3-NP treatment. Further indications of hMTH1-mediated mitochondrial protection are the partial reversion of 3-NP-induced alterations in mitochondrial morphology and the modulation of DRP1 and MFN1 proteins, which control fusion/fission rates of mitochondria. Finally, in line with the in vitro findings, upon 3-NP in vivo treatment, 8-hydroxyguanine levels in mitochondrial DNA from heart, muscle and brain are significantly lower in transgenic hMTH1-expressing mice than in wild-type animals. ► hMTH1 provides defence against cell death in mutant htt-expressing striatal cells ► hMTH1 improves mitochondrial functionality in mutant htt-expressing striatal cells ► hMTH1 protects in vivo mitochondria from endogenous and 3-NP induced oxidation
登录
查看更多内容
影响因子：
5.4
作者：
Firdaus, Wance J. J.;Wyttenbach, Andreas;Arrigo, Andre-Patrick
通讯作者：
Arrigo, Andre-Patrick
影响因子：
5.3
作者：
Kajitani, K;Yamaguchi, H;Nakabeppu, Y
通讯作者：
Nakabeppu, Y
影响因子：
2.9
作者：
Hayakawa, H;Hofer, A;Sekiguchi, M
通讯作者：
Sekiguchi, M
影响因子：
3.5
作者：
Gines, S;Seong, IS;MacDonald, ME
通讯作者：
MacDonald, ME
影响因子：
7.4
作者：
Hori, Mika;Satou, Kazuya;Kamiya, Hiroyuki
通讯作者：
Kamiya, Hiroyuki