Simon David K, Lin Michael T, Zheng Leiya, Liu Guang-Jun, Ahn Colette H, Kim Lauren M, Mauck William M, Twu Florence, Beal M Flint, Johns Donald R
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Neurobiol Aging. 2004 Jan;25(1):71-81. doi: 10.1016/s0197-4580(03)00037-x.
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.
大脑中线粒体DNA（mtDNA）的氧化损伤随年龄增长而增加，并可诱导G:C到T:A以及T:A到G:C的点突变。尽管在任何特定位点这种情况都很罕见，但由氧化损伤或其他机制诱导的多个体细胞mtDNA突变可能会随着年龄增长在大脑中积累，从而可能在衰老和神经退行性疾病中发挥作用。然而，此前尚无研究对大脑中mtDNA点突变亚型的总负担进行量化。通过使用一种高度灵敏的克隆和测序策略，我们发现额叶皮质（FCtx）中G:C到T:A以及T:A到G:C的颠换和所有点突变的总体水平随年龄增长而增加。在黑质（SN）中，年轻对照组的点突变总体水平与老年受试者SN或FCtx中的水平相似。根据我们的数据推断，老年受试者每个线粒体基因组平均有2.7个（FCtx）到3.2个（SN）体细胞点突变。帕金森病（PD）患者与年龄匹配的对照组在体细胞突变水平上没有显著差异。这些结果表明，单个罕见的mtDNA点突变在老年受试者的FCtx和SN中达到了很高的总体负担。
