Cantuti-Castelvetri Ippolita, Lin Michael T, Zheng Kangni, Keller-McGandy Christine E, Betensky Rebecca A, Johns Donald R, Beal M Flint, Standaert David G, Simon David K
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Neurobiol Aging. 2005 Nov-Dec;26(10):1343-55. doi: 10.1016/j.neurobiolaging.2004.11.008. Epub 2004 Dec 29.
Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p=0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p=0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.
体细胞线粒体DNA（mtDNA）点突变在大脑中达到很高水平。然而，积累突变的细胞类型以及单个细胞内的突变模式尚不清楚。我们对来自6名对照受试者尸检人类黑质的28个单个神经元和18个单个神经胶质细胞中的体细胞mtDNA突变进行了定量分析。神经元和神经胶质细胞均含有带有体细胞突变的mtDNA。单个神经元每百万碱基对中体细胞mtDNA点突变的几何平均数（95%置信区间）为200.3（152.9 - 262.4），而单个神经胶质细胞为133.8（97.5 - 184.9）（p = 0.0251）。如果在同一细胞中多次检测到的突变只计一次，那么每百万碱基对的平均突变水平在单个神经元中（146.9；124.0 - 174.2）仍高于单个神经胶质细胞（100.5；81.5 - 126.5；p = 0.009）。来自同一受试者的不同细胞中存在多个不同的体细胞点突变。这些突变大多数在单个细胞中以低水平存在（占mtDNA分子的比例小于10 - 20%），但总体突变水平较高，尤其是在神经元中。这些突变可能在正常衰老和神经退行性疾病过程中导致脑功能变化。
