Abstract
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.
Highlights
Alzheimer’s disease (AD) has been recognized since the beginning of the 20th century, we still have little information about the etiology at the molecular level
We propose that an imbalance in oxidative stress and DNA repair responses influence neurodegeneration in AD
Lower mRNA levels of RPA1 and ERCC1 were observed in the blood samples of AD patients compared to healthy controls (HC). These findings suggest that decreased DNA repair of replication by the Replication Protein A (RPA)-complex and decreased endonuclease function of the XPF-ERCC1-complex potentially could be a part of the pathogenesis of AD
Summary
Alzheimer’s disease (AD) has been recognized since the beginning of the 20th century, we still have little information about the etiology at the molecular level. We propose that an imbalance in oxidative stress and DNA repair responses influence neurodegeneration in AD. The NER pathway repairs bulky helix-distorting damage events in DNA, which can be caused by several various sources including UV radiation, chemical adducts and oxidative stress. NER is one of the most well-characterized mechanisms of DNA repair, and defects in the NER pathway are recognized causes of several neurodegenerative diseases, such as Cockayne syndrome (CS), trichothiodystrophy and some subtypes of xeroderma pigmentosum (XP) [6,17]. It is proposed that NER-inflicted neurodegeneration most likely is caused by endogenous DNA lesions [1], since exogenous stress such as UV radiation does not directly affect the brain and most chemical adducts do not cross the blood-brain barrier. Endogenous DNA lesions are most commonly caused by reactive oxygen species (ROS) and as a consequence, damaged macromolecules including DNA are generated
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