Jensen Helge Leander B, Lillenes Meryl S, Rabano Alberto, Günther Clara-Cecilie, Riaz Tahira, Kalayou Shewit T, Ulstein Ingun D, Bøhmer Thomas, Tønjum Tone
Department of Microbiology, University of Oslo, Oslo, Norway.
Department of Microbiology, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, Oslo, Norway.
Neurosci Lett. 2018 Apr 13;672:53-58. doi: 10.1016/j.neulet.2018.02.043. Epub 2018 Feb 21.
Age-related changes are increased in patients with Alzheimer's disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain.
阿尔茨海默病（AD）患者与年龄相关的变化会增加，包括氧化应激和DNA损伤。我们提出，基因毒性应激和DNA修复反应在AD发病机制中影响神经退行性变。在此，我们聚焦于核苷酸切除修复（NER）。采用实时定量PCR和质谱法来测定所选NER组分的表达水平。评估了AD或轻度认知障碍患者以及健康对照（HC）的四个脑区的血液和脑组织中编码NER蛋白RAD23B、RPA1、ERCC1、PCNA和LIG3的基因以及与NER相互作用的碱基切除修复蛋白MPG的mRNA水平。NER的mRNA水平在脑组织中显著高于血液。此外，与HC相比，AD患者额叶皮质中的LIG3 mRNA水平更高，而内嗅皮质中的MPG和LIG3以及小脑中的RPA1的mRNA水平在AD患者中低于HC。在血液中，AD患者的RPA1和ERCC1 mRNA水平低于HC。脑区之间NER组分基因表达的改变与AD相关，将DNA修复与AD发病机制联系起来，并表明NER在大脑中具有独特作用。
