Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease
Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease
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DOI：
10.1016/s0197-4580(03)00037-x
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发表时间：
2004-01-01
影响因子：
4.2
通讯作者：
Johns, DR
中科院分区：
文献类型：
--
作者：
Simon, DK;Lin, MT;Johns, DR
线粒体DNA的氧化损伤(MtDNA)在大脑中随着年龄的增长而增加，并可导致G：C到T：A和T：A到G：C的点突变。虽然在任何特定部位都很少见，但由氧化损伤或其他机制引起的多个体细胞mtDNA突变可能会随着年龄的增长在大脑中积累，从而可能在衰老和神经退行性疾病中发挥作用。然而，先前没有研究量化mtDNA点突变亚型在大脑中的总负担。使用高度敏感的克隆和测序策略，我们发现在额叶皮质(FCtx)，G：C到T：A和T：A到G：C的颠换和所有点突变的总水平随着年龄的增长而增加。在黑质(SN)，年轻对照组的点突变的总水平与老年受试者黑质或FCtx的水平相似。根据我们的数据推断，在老年受试者中，每个线粒体基因组平均有2.7(FCtx)到3.2(SN)个体细胞点突变。帕金森病(PD)患者和年龄匹配的对照组之间的体细胞突变水平没有显著差异。这些结果表明，在老年受试者的FCtx和SN中，个别罕见的mtDNA点突变达到了很高的总体负担。(C)2003 Elsevier Science Inc.保留所有权利。
Oxidative damage to mitochondrial DNA (mtDNA) increases with age in the brain and can induce G:C to T:A and T:A to G:C point mutations. Though rare at any particular site, multiple somatic mtDNA mutations induced by oxidative damage or by other mechanisms may accumulate with age in the brain and thus could play a role in aging and neurodegenerative diseases. However, no prior study has quantified the total burden of mtDNA point mutation subtypes in the brain. Using a highly sensitive cloning and sequencing strategy, we find that the aggregate levels of G:C to T:A and T:A to G:C transversions and of all point mutations increase with age in the frontal cortex (FCtx). In the substantia nigra (SN), the aggregate levels of point mutations in young controls are similar to the levels in the SN or FCtx of elderly subjects. Extrapolation from our data suggests an average of 2.7 (FCtx) to 3.2 (SN) somatic point mutations per mitochondrial genome in elderly subjects. There were no significant differences between Parkinson's disease (PD) patients and age-matched controls in somatic mutation levels. These results indicate that individually rare mtDNA point mutations reach a high aggregate burden in FCtx and SN of elderly subjects. (C) 2003 Elsevier Science Inc. All rights reserved.