Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.
Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin.
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DOI：
10.1371/journal.pone.0057932
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Johnson GV
中科院分区：
文献类型：
--
作者：
Jin YN;Yu YV;Gundemir S;Jo C;Cui M;Tieu K;Johnson GV
亨廷顿病（Huntington disease，HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白（Huntingtin，Htt）中多聚谷氨酰胺异常扩增引起。受损的氧化应激防御系统已成为HD发病机制的一个促成因素。事实上，Nrf 2途径的激活，其在介导抗氧化反应中起着重要作用，已被认为是治疗HD的治疗策略。鉴于线粒体动力学损伤和氧化应激增加之间存在相互关系，在本研究中，我们研究了突变体Htt（mHtt）对这两个参数的影响。与STHdhQ 7/Q7细胞（表达野生型Htt的纹状体细胞）相比，STHdhQ 111/Q111细胞（表达mHtt的纹状体细胞）显示出更多片段化的线粒体，同时分别伴随着线粒体分裂和融合的关键调节因子Drp 1和Opa 1的表达水平的改变。使用细胞融合和线粒体靶向光可切换Dendra的线粒体动力学研究揭示，STHdhQ 111/Q111细胞中线粒体融合显著降低。氧化应激导致含有肿胀线粒体的STHdhQ 111/Q111细胞的数量急剧增加，而STHdhQ 7/Q7细胞仅显示碎片化线粒体的数量增加。mHtt表达导致Nrf 2活性降低，并且在STHdhQ 111/Q111细胞中氧化剂tBHQ对Nrf 2途径的激活显著受损。Nrf 2表达在两种细胞类型之间没有差异，但STHdhQ 111/Q111细胞显示Nrf 2信号的关键调节剂Keap 1和p62的表达降低。此外，STHdhQ 111/Q111细胞表现出自噬增加，而STHdhQ 7/Q7细胞中自噬激活的基础水平较低。这些结果表明，mHtt破坏Nrf 2信号，这有助于受损的线粒体动力学，并可能提高STHDhQ 111/Q111细胞对氧化应激的敏感性。
Huntington disease (HD) is an inherited neurodegenerative disease resulting from an abnormal expansion of polyglutamine in huntingtin (Htt). Compromised oxidative stress defense systems have emerged as a contributing factor to the pathogenesis of HD. Indeed activation of the Nrf2 pathway, which plays a prominent role in mediating antioxidant responses, has been considered as a therapeutic strategy for the treatment of HD. Given the fact that there is an interrelationship between impairments in mitochondrial dynamics and increased oxidative stress, in this present study we examined the effect of mutant Htt (mHtt) on these two parameters. STHdhQ111/Q111 cells, striatal cells expressing mHtt, display more fragmented mitochondria compared to STHdhQ7/Q7 cells, striatal cells expressing wild type Htt, concurrent with alterations in the expression levels of Drp1 and Opa1, key regulators of mitochondrial fission and fusion, respectively. Studies of mitochondrial dynamics using cell fusion and mitochondrial targeted photo-switchable Dendra revealed that mitochondrial fusion is significantly decreased in STHdhQ111/Q111 cells. Oxidative stress leads to dramatic increases in the number of STHdhQ111/Q111 cells containing swollen mitochondria, while STHdhQ7/Q7 cells just show increases in the number of fragmented mitochondria. mHtt expression results in reduced activity of Nrf2, and activation of the Nrf2 pathway by the oxidant tBHQ is significantly impaired in STHdhQ111/Q111 cells. Nrf2 expression does not differ between the two cell types, but STHdhQ111/Q111 cells show reduced expression of Keap1 and p62, key modulators of Nrf2 signaling. In addition, STHdhQ111/Q111 cells exhibit increases in autophagy, whereas the basal level of autophagy activation is low in STHdhQ7/Q7 cells. These results suggest that mHtt disrupts Nrf2 signaling which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in STHdhQ111/Q111 cells.
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影响因子：
10.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.172398899
发表时间：
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