Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease.
Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease.
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DOI：
10.1038/ncomms13548
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发表时间：
2016-11-22
影响因子：
16.6
通讯作者：
Tzoulis, Charalampos
中科院分区：
文献类型：
--
作者：
Dolle, Christian;Flones, Irene;Nido, Gonzalo S.;Miletic, Hrvoje;Osuagwu, Nelson;Kristoffersen, Stine;Lilleng, Peer K.;Larsen, Jan Petter;Tysnes, Ole-Bjorn;Haugarvoll, Kristoffer;Bindoff, Laurence A.;Tzoulis, Charalampos
体细胞线粒体DNA(MtDNA)突变增加会导致小鼠过早衰老，随着年龄的增长和帕金森病(PD)等神经退行性疾病的发生，mtDNA损伤会在人脑中积累。在这里，我们研究了帕金森病患者和神经学健康对照组黑质多巴胺能神经元和其他脑区的mtDNA变化的完整谱，包括缺失、拷贝数变化和点突变。我们发现，在健康个体的黑质多巴胺能神经元中，mtDNA拷贝数随着年龄的增长而增加，尽管存在累积的缺失，但仍维持着野生型mtDNA种群的池。然而，这种上调在帕金森病患者中没有发生，导致野生型mtDNA种群的枯竭。相比之下，帕金森病患者神经元mtDNA点突变负荷并未增加。我们的研究结果表明，线粒体DNA稳态失调是帕金森病神经元丢失发病机制中的一个关键过程。线粒体DNA(MtDNA)的累积损伤发生在衰老过程和神经退行性疾病中。在这里，作者表明，在健康人的黑质中，mtDNA拷贝数随着年龄的增加而增加，但在帕金森病患者中不是这样。
Increased somatic mitochondrial DNA (mtDNA) mutagenesis causes premature aging in mice, and mtDNA damage accumulates in the human brain with aging and neurodegenerative disorders such as Parkinson disease (PD). Here, we study the complete spectrum of mtDNA changes, including deletions, copy-number variation and point mutations, in single neurons from the dopaminergic substantia nigra and other brain areas of individuals with Parkinson disease and neurologically healthy controls. We show that in dopaminergic substantia nigra neurons of healthy individuals, mtDNA copy number increases with age, maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. This upregulation fails to occur in individuals with Parkinson disease, however, resulting in depletion of the wild-type mtDNA population. By contrast, neuronal mtDNA point mutational load is not increased in Parkinson disease. Our findings suggest that dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease. Accumulated damage to mitochondrial DNA (mtDNA) occurs during the ageing process and neurodegenerative disease. Here, the authors show that mtDNA copy number increases in an age-dependent manner in substantia nigra of healthy individuals, but not in individuals with Parkinson disease.
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