Ramos Amanda, Kazachkova Nadiya, Silva Francisca, Maciel Patrícia, Silva-Fernandes Anabela, Duarte-Silva Sara, Santos Cristina, Lima Manuela
Centre of Research in Natural Resources (CIRN), Department of Biology, University of the Azores, Ponta Delgada, Portugal,
J Mol Neurosci. 2015 Feb;55(2):449-53. doi: 10.1007/s12031-014-0360-1. Epub 2014 Jul 8.
Mitochondrial dysfunction has been associated with late onset neurodegenerative disorders, among which is Machado-Joseph disease (MJD/SCA3). In a previous study, using a transgenic mouse model of MJD, we reported a decrease in mitochondrial DNA (mtDNA) copy number and an accumulation of the 3876-bp deletion with age and with phenotype development. We extended this study by analyzing the pattern of mtDNA depletion and the accumulation of the 3876-bp deletion in 12 older transgenic (TG) and 4 wild-type (wt) animals, and by investigating the accumulation of somatic mutations in the D-loop region in 76 mice (42 TG and 34 wt). mtDNA damage was studied in TG and wt mice at different ages and tissues (blood, pontine nuclei, and hippocampus). Results for older mice demonstrate an accumulation of the mtDNA 3867-bp deletion with age, which was more pronounced in TG animals. Furthermore, the tendency for mtDNA copy number decrease with age, in all analyzed tissues of TG and wt animals, was also confirmed. No point mutations were detected in the D-loop, neither in TG nor wt animals, in any of the tissues analyzed. Due to the absence of mtDNA somatic mutations, we can suggest that mtDNA point mutation accumulation cannot be used to monitor the development and progression of the phenotype in this mouse model and likely in any MJD mice model. The present results further confirm not only the association between mtDNA alterations (copy number and deletions) and age, but also between such alterations and the expression of the mutant ataxin-3 in TG mice.
线粒体功能障碍与迟发性神经退行性疾病有关，其中包括马查多-约瑟夫病（MJD/SCA3）。在先前的一项研究中，我们使用MJD转基因小鼠模型，报告了线粒体DNA（mtDNA）拷贝数随年龄和表型发展而减少，以及3876bp缺失的积累。我们通过分析12只老年转基因（TG）和4只野生型（wt）动物中mtDNA消耗模式和3876bp缺失的积累，并研究76只小鼠（42只TG和34只wt）D环区域体细胞突变的积累，扩展了这项研究。在不同年龄和组织（血液、脑桥核和海马体）的TG和wt小鼠中研究了mtDNA损伤。老年小鼠的结果表明，mtDNA 3867bp缺失随年龄积累，在TG动物中更明显。此外，还证实了TG和wt动物所有分析组织中mtDNA拷贝数随年龄下降的趋势。在任何分析的组织中，TG和wt动物的D环均未检测到点突变。由于不存在mtDNA体细胞突变，我们可以认为，在该小鼠模型以及可能的任何MJD小鼠模型中，mtDNA点突变积累不能用于监测表型的发展和进展。目前的结果不仅进一步证实了mtDNA改变（拷贝数和缺失）与年龄之间的关联，还证实了这种改变与TG小鼠中突变ataxin-3表达之间的关联。
