Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients.
Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients.
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DOI：
10.1038/s41598-018-27985-y
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发表时间：
2018-06-29
影响因子：
4.6
通讯作者：
Eide L
中科院分区：
文献类型：
--
作者：
Askeland G;Dosoudilova Z;Rodinova M;Klempir J;Liskova I;Kuśnierczyk A;Bjørås M;Nesse G;Klungland A;Hansikova H;Eide L
亨廷顿病（HD）是一种进行性神经退行性疾病，主要影响基底神经节，由亨廷顿基因中CAG重复序列的扩增引起。除了CAG长度测定外，线粒体和核DNA（mtDNA和nDNA）的相关参数尚未被证明是该疾病及未来治疗具有代表性的生物标志物。在此，我们发现与对照组相比，亨廷顿病患者外周血单个核细胞（PBMCs）中与有氧代谢相关的基因普遍受到抑制。在亨廷顿病中，复合物II亚基SDHB水平降低，但尚不足以影响复合物II的活性。然而，我们发现与线粒体生物发生相关的因子水平降低，且亨廷顿病中线粒体DNA损伤频率相应降低，这意味着线粒体活动存在早期缺陷。与mtDNA相反，亨廷顿病患者的nDNA的修饰程度是对照组的四倍，这表明亨廷顿病中nDNA的完整性严重受损。有趣的是，nDNA损伤水平与总功能能力（TFC）评分呈负相关，TFC评分是一种已确定的亨廷顿病功能评分。我们的数据表明，PBMCs是监测亨廷顿病进展的一个有前景的来源，并强调了nDNA损伤以及线粒体和核基因组不同的反应，这些代表了亨廷顿病早期的细胞损伤。
Huntington’s disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarkers for disease and future therapy. Here, we identified a general suppression of genes associated with aerobic metabolism in peripheral blood mononuclear cells (PBMCs) from HD patients compared to controls. In HD, the complex II subunit SDHB was lowered although not sufficiently to affect complex II activity. Nevertheless, we found decreased level of factors associated with mitochondrial biogenesis and an associated dampening of the mitochondrial DNA damage frequency in HD, implying an early defect in mitochondrial activity. In contrast to mtDNA, nDNA from HD patients was four-fold more modified than controls and demonstrated that nDNA integrity is severely reduced in HD. Interestingly, the level of nDNA damage correlated inversely with the total functional capacity (TFC) score; an established functional score of HD. Our data show that PBMCs are a promising source to monitor HD progression and highlights nDNA damage and diverging mitochondrial and nuclear genome responses representing early cellular impairments in HD.
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
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作者：
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