Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington's disease.
Mitochondrial DNA damage is a hallmark of chemically induced and the R6/2 transgenic model of Huntington's disease.
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DOI：
10.1016/j.dnarep.2008.09.004
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发表时间：
2009-01-01
期刊：
影响因子：
3.8
通讯作者：
Ayala-Torres, Sylvette
中科院分区：
文献类型：
--
作者：
Acevedo-Torres, Karina;Berrios, Lexsy;Rosario, Nydia;Dufault, Vanessa;Skatchkov, Serguei;Eaton, Misty J.;Torres-Ramos, Carlos A.;Ayala-Torres, Sylvette
许多形式的神经变性与氧化应激和线粒体功能障碍有关。线粒体是氧化损伤的主要靶点，然而，尚不清楚线粒体DNA（mtDNA）损伤和/或其缺乏修复是否是在亨廷顿病（HD）中观察到的延迟发作的主要事件。我们推测，年龄依赖性增加的线粒体DNA损伤有助于线粒体功能障碍的HD。研究了两种HD小鼠模型，即3-硝基丙酸（3-NPA）化学诱导模型和亨廷顿基因中含有115-150个CAG重复的R6/2品系HD转基因小鼠。线粒体毒素3-NPA抑制电子传递系统的复合物II，并导致类似于人类和实验动物纹状体中的HD的神经变性。我们通过定量PCR（QPCR）测定了5个月和24个月龄未经处理和3-NPA处理的C57 BL/6小鼠纹状体中的核和mtDNA损伤。衰老导致细胞核和线粒体基因组的损伤增加。3-NPA对5月龄小鼠线粒体DNA的损伤比对核DNA的损伤多4-6倍，且这种损伤在48 h内得到修复。在24个月大的小鼠中，3 NPA引起等量的核和线粒体损伤，这种损伤在两个基因组中持续48小时。QPCR分析显示，7-12周龄R6/2小鼠纹状体和大脑皮质中mtDNA损伤水平逐渐增加。纹状体对mtDNA的损伤是核基因的8倍。这些数据表明，mtDNA损伤是HD相关神经退行性变的早期生物标志物，并支持mtDNA损伤可能导致HD发病机制的假设。
Many forms of neurodegeneration are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage, however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are primary events in the delayed onset observed in Huntington’s disease (HD). We hypothesize that an age-dependent increase in mtDNA damage contributes to mitochondrial dysfunction in HD. Two HD mouse models were studied, the 3-nitropropionic acid (3-NPA) chemically induced model and the HD transgenic mice of the R6/2 strain containing 115–150 CAG repeats in the huntingtin gene. The mitochondrial toxin 3-NPA inhibits complex II of the electron transport system and causes neurodegeneration that resembles HD in the striatum of human and experimental animals. We measured nuclear and mtDNA damage by quantitative PCR (QPCR) in striatum of 5- and 24-month-old untreated and 3-NPA treated C57BL/6 mice. Aging caused an increase in damage in both nuclear and mitochondrial genomes. 3-NPA induced 4–6 more damage in mtDNA than nuclear DNA in 5-month-old mice, and this damage was repaired by 48 h in the mtDNA. In 24-month-old mice 3NPA caused equal amounts of nuclear and mitochondrial damage and this damage persistent in both genomes for 48 h. QPCR analysis showed a progressive increase in the levels of mtDNA damage in the striatum and cerebral cortex of 7–12-week-old R6/2 mice. Striatum exhibited eight-fold more damage to the mtDNA compared with a nuclear gene. These data suggest that mtDNA damage is an early biomarker for HD-associated neurodegeneration and supports the hypothesis that mtDNA lesions may contribute to the pathogenesis observed in HD.
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