Instytut Podstawowych Problemów Techniki

Streszczenie:

Background: Increased oxidative damage to DNA is one of the pathways involved in Alzheimer's disease (AD). Insufficient base excision repair (BER) is in part responsible for increased oxidative DNA damage. The aim of the present study was to assess the effect of polymorphic variants of BER-involved genes and the peripheral markers of DNA damage and repair in patients with AD. Material and Methods: Comet assays and TaqMan probes were used to assess DNA damage, BER efficiency and polymorphic variants of 12 BER genes in blood samples from 105 AD patients and 130 controls. The DNA repair efficacy (DRE) was calculated according to a specific equation. Results: The levels of endogenous and oxidative DNA damages were higher in AD patients than controls. The polymorphic variants of XRCC1 c.580C>T XRCC1 c.1196A>G and OGG1 c.977C>G are associated with increased DNA damage in AD. Conclusion: Our results show that oxidative stress and disturbances in DRE are particularly responsible for the elevated DNA lesions in AD. The results suggest that oxidative stress and disruption in DNA repair may contribute to increased DNA damage in AD patients and risk of this disease. In addition, disturbances in DRE may be associated with polymorphisms of OGG1 and XRCC1.

Słowa kluczowe:

DNA damage, DNA base excision repair, Alzheimer's disease risk, Dementia, Oxidative stress

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Streszczenie:

Evidence indicates that oxidative stress contributes to neuronal cell death in Alzheimer's disease (AD). Increased oxidative DNA damage I, as measured with 8-oxoguanine (8-oxoG), and reduced capacity of proteins responsible for removing of DNA damage, including 8-oxoguanine DNA glycosylase 1 (OGG1), were detected in brains of AD patients. In the present study we assessed peripheral blood biomarkers of oxidative DNA damage, i.e. 8-oxoG and OGG1, in AD diagnosis, by comparing their levels between the patients and the controls. Our study was performed on DNA and serum isolated from peripheral blood taken from 100 AD patients and 110 controls. For 8-oxoG ELISA was employed. The OGG1 level was determined using ELISA and Western blot technique. Levels of 8-oxoG were significantly higher in DNA of AD patients. Both ELISA and Western blot showed decreased levels of OGG1 in serum of AD patients. Our results show that oxidative DNA damage biomarkers detected in peripheral tissue could reflect the changes occurring in the brain of patients with AD. These results also suggest that peripheral blood samples may be useful to measure oxidative stress biomarkers in AD.

Słowa kluczowe:

Alzheimer's disease, Oxidative stress, Oxidative DNA damage, 7 8-dihydrodeoxyguanosine (8-oxoG), DNA base excision repair, 8-oxoguanine DNA glycosylase 1 (OGG1)

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Streszczenie:

Background: One of the factors that contribute to Alzheimer's disease (AD) is the DNA damage caused by oxidative stress and inflammation that occurs in nerve cells. It has been suggested that the risk of AD may be associated with an age dependent reduction of the DNA repair efficiency. Base excision repair (BER) is, among other things, a main repair system of oxidative DNA damage. One of the reasons for the reduced efficiency of this system may be single-nucleotide polymorphisms (SNP) of the genes encoding its proteins. Methods: DNA for genotyping was obtained from the peripheral blood of 281 patients and 150 controls. In the present study, we evaluated the impact of 8 polymorphisms of 6 BER genes on the AD risk. We analyzed the following SNP: c.-468T>G and c.444T>G of APEX1, c.*50C>T and c.*83A>C of LIG3, c.977C>G of OGG1, c.*283C>G of NEIL1, c.-441G>A of FEN1, and c.-7C>T of LIG1. Results: We showed that the LIG1 c.-7C>T A/A and LIG3 c.*83A>C A/C variants increased, while the APEX1 c.444T>G G/T, LIG1 c.-7C>T G/, LIG3 c.*83A>C C/C variants reduced, the AD risk. We also evaluated the relation between gene-gene interactions and the AD risk. We showed that combinations of certain BER gene variants such as c.977C>Gxc.*50C>T CC/CT, c./111T>Gxc.*50C>T GG/CT, c.-468T>Gxc.*50C>T GG/CT, c.-441G>Ac.*50C>Txc.*50C>T GG/CT, c.*83A>Cx c.*50C>T CT/AC, and c.-7C>Txc.*50C>T CT/GG can substantially positively modulate the risk of AD. Conclusions: In conclusion, we revealed that polymorphisms of BER genes may have a significant effect on the AD risk, and the presence of polymorphic variants may be an important marker for AD.

Słowa kluczowe:

Alzheimer's disease, Base excision repair, Polymorphisms

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Streszczenie:

Background: Depressive disorder, including recurrent type (rDD), is accompanied by increased oxidative stress and activation of inflammatory pathways, which may induce DNA damage. This thesis is supported by the presence of increased levels of DNA damage in depressed patients. Such DNA damage is repaired by the base excision repair (BER) pathway. BER efficiency may be influenced by polymorphisms in BER-related genes. Therefore, we genotyped nine single-nucleotide polymorphisms (SNPs) in six genes encoding BER proteins.

Material/Methods: Using TaqMan, we selected and genotyped the following SNPs: c.-441G>A (rs174538) of FEN1, c.2285T>C (rs1136410) of PARP1, c.580C>T (rs1799782) and c.1196A>G (rs25487) of XRCC1, c.*83A>C (rs4796030) and c.*50C>T (rs1052536) of LIG3, c.-7C>T (rs20579) of LIG1, and c.-468T>G (rs1760944) and c.444T>G (rs1130409) of APEX1 in 599 samples (288 rDD patients and 311 controls).

Results: We found a strong correlation between rDD and both SNPs of LIG3, their haplotypes, as well as a weaker association with the c.-468T>G of APEXI which diminished after Nyholt correction. Polymorphisms of LIG3 were also associated with early onset versus late onset depression, whereas the c.-468T>G polymorphism showed the opposite association.

Conclusions: The SNPs of genes involved in the repair of oxidative DNA damage may modulate rDD risk. Since this is an exploratory study, the results should to be treated with caution and further work needs to be done to elucidate the exact involvement of DNA damage and repair mechanisms in the development of this disease.

Słowa kluczowe:

Depression, DNA Repair, Inflammation, Oxidative Stress, Polymorphism, Single Nucleotide

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Streszczenie:

Background: An elevated levels oxidative modified DNA bases and a decreased efficiency of oxidative DNA damage repair were found in patients with depression disorders, including recurrent type (rDD). The glycosylases are involved in base excision repair (BER), which eliminates oxidative DNA damage. Therefore, we genotyped the single nucleotide polymorphisms (SNPs) of genes encoding three glycosylases: hOGG1, MUTYH and NEILL

Methods: We selected three polymorphisms: c.977C > G - hOGG1 (rs1052133), c.972G > C - MUTYH (rs3219489) and c.*589G > C - NEIL1 (rs4462560). A total of 555 DNA samples (257 cases and 298 controls) were genotyped using TaqMan probes.

Results: The C/C genotype and allele C of the c.*589G > C decreased the risk of rDD occurrence, while the G/G genotype and allele G of the same SNP increased the risk. This polymorphism had a stronger association with early-onset depression (patients with first episode <35 years of age) than with late onset depression (first episode >= 35 years of age). We did not find any significant differences in distribution of alleles and genotypes of other SNPs; however, the G/G genotype of the c.972G > C increased the risk of late onset rDD. We also found that combined genotype C/C-C/C of c.977C > G and c.*589G > C significantly reduced the risk of rDD.

Limitations: Limited sample size and ethnic homogeneity of the studied population.

Conclusion: This is the first study to show that SNPs of genes involved in DNA repair, particularly in BER pathway, may modulate the risk of rDD. These results further support the hypothesis on the involvement of DNA repair mechanisms in pathogenesis of depression.

Słowa kluczowe:

Depression, Glycosylases, BER, DNA repair, DNA damage

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Streszczenie:

Background: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimer's disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. Methods: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e.XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. Results: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762,95% Cl: 1.793-7.8911. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485,95% Cl: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR =4.159, 95% Cl: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240,95% Cl: 0.114-0.556) of AD. Conclusions: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk.

Słowa kluczowe:

Alzheimer's disease, Base excision repair, Polymorphisms

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Streszczenie:

Background: Depressive disorder (DD), including recurrent DD (rDD), is a severe psychological disease, which affects a large percentage of the world population. Although pathogenesis of the disease is not known, a growing body of evidence shows that inflammation together with oxidative stress may contribute to development of DD. Since reactive oxygen species produced during stress may damage DNA, we wanted to evaluate the extent of DNA damage and efficiency of DNA repair in patients with depression.

Material/Methods: We measured and compared the extent of endogenous DNA damage - single- and double-strand breaks, alkali-labile sites, and oxidative damage of the pyrimidines and purines - in peripheral blood mononuclear cells isolated from rDD patients (n=40) and healthy controls (n=46) using comet assay. We also measured DNA damage evoked by hydrogen peroxide and monitored changes in DNA damage during repair incubation.

Results: We found an increased number DNA breaks, alkali-labile sites, and oxidative modification of DNA bases in the patients compared to the controls. Exposure to hydrogen peroxide evoked the same increased damage in both groups. Examination of the repair kinetics of both groups revealed that the lesions were more efficiently repaired in the controls than in the patients.

Conclusions: For the first time we showed that patients with depression, compared with non-depresses individuals, had more DNA breaks, alkali-labile sites, and oxidative DNA damage, and that those lesions may be accumulated by impairments of the DNA repair systems. More studies must be conducted to elucidate the role of DNA damage and repair in depression.

Słowa kluczowe:

Depression, DNA Damage, DNA Repair, Oxidative Stress, Reactive Oxygen Species

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