Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease
Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease
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DOI：
10.1093/hmg/ddq306
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发表时间：
2010-10-15
影响因子：
3.5
通讯作者：
Ferrante, Robert J.
中科院分区：
文献类型：
--
作者：
Kim, Jinho;Moody, Jennifer P.;Ferrante, Robert J.
尽管在亨廷顿病（HD）中从基因突变到选择性新纹状体神经变性的直接致病途径尚不清楚，但据报道在这种神经系统疾病的发病机制中起重要作用的一个假定的病理机制是线粒体功能障碍。我们研究了线粒体优先脆弱的纹状体钙结合蛋白阳性神经元中的中度至重度HD患者，使用抗线粒体标记物的COX 2，SOD 2和细胞色素c。结合钙结合蛋白和线粒体标记物免疫荧光显示，棘状纹状体神经元的线粒体数量显着和渐进的等级依赖性减少，大小有显着变化。与线粒体损失一致，使用Western分析，COX 2蛋白水平降低，与疾病严重程度相对应。此外，线粒体转录因子A（一种线粒体DNA的调节因子）和过氧化物酶体增殖物激活受体-共激活因子γ-1 α（一种能量代谢和线粒体生物合成的关键转录调节因子）也随着疾病严重程度的增加而显著降低。观察到线粒体动力学的异常，显示出分裂蛋白Drp 1的显著增加和融合蛋白mitofusin 1的表达的减少。最后，在HD尾状核标本中的线粒体PCR阵列分析显示，参与线粒体定位，膜转位和极化和运输的线粒体紊乱的蛋白质的mRNA表达增加。这些发现表明，在HD中存在线粒体丢失和线粒体形态发生改变，线粒体分裂增加，融合减少。这些发现进一步证明了线粒体功能障碍在HD的发病机制中起着关键作用。
Although a direct causative pathway from the gene mutation to the selective neostriatal neurodegeneration remains unclear in Huntington's disease (HD), one putative pathological mechanism reported to play a prominent role in the pathogenesis of this neurological disorder is mitochondrial dysfunction. We examined mitochondria in preferentially vulnerable striatal calbindin-positive neurons in moderate-to-severe grade HD patients, using antisera against mitochondrial markers of COX2, SOD2 and cytochrome c. Combined calbindin and mitochondrial marker immunofluorescence showed a significant and progressive grade-dependent reduction in the number of mitochondria in spiny striatal neurons, with marked alteration in size. Consistent with mitochondrial loss, there was a reduction in COX2 protein levels using western analysis that corresponded with disease severity. In addition, both mitochondrial transcription factor A, a regulator of mtDNA, and peroxisome proliferator-activated receptor-co-activator gamma-1 alpha, a key transcriptional regulator of energy metabolism and mitochondrial biogenesis, were also significantly reduced with increasing disease severity. Abnormalities in mitochondrial dynamics were observed, showing a significant increase in the fission protein Drp1 and a reduction in the expression of the fusion protein mitofusin 1. Lastly, mitochondrial PCR array profiling in HD caudate nucleus specimens showed increased mRNA expression of proteins involved in mitochondrial localization, membrane translocation and polarization and transport that paralleled mitochondrial derangement. These findings reveal that there are both mitochondrial loss and altered mitochondrial morphogenesis with increased mitochondrial fission and reduced fusion in HD. These findings provide further evidence that mitochondrial dysfunction plays a critical role in the pathogenesis of HD.