8-hydroxyguanine and Neurodegenerative-Diseases

Base excision repair (BER) is the major pathway responsible for averting the mutagenic and cytotoxic effects of spontaneous hydrolytic, oxidative, and non-enzymatic alkylation DNA damage. In particular, this pathway recognizes and repairs base modifications, such as uracil and 8-hydroxyguanine, as well as abasic sites and DNA single-strand breaks. In this review, we outline the basic mechanics of the BER process, and describe the potential association of this pathway with aging and age-related disease, namely cancer and neurodegeneration.

Topics: Aging; DNA Repair; Guanine; Humans; Mitochondria; Neoplasms; Neurodegenerative Diseases

Topics: Animals; DNA Damage; DNA Glycosylases; DNA Repair Enzymes; DNA, Mitochondrial; Genome; Guanine; Humans; Mitochondria; Neurodegenerative Diseases; Nucleotides; Oxidative Stress; Phosphoric Monoester Hydrolases

Formaldehyde is an environmental and occupational chemical carcinogen implicated in the damage of proteins and nucleic acids. However, whether formaldehyde provokes modifications of RNAs such as 8-oxo-7,8-dihydroguanine (8-oxoG) and the role that these modifications play on conferring long-term adverse health effects remains unexplored. Here, we profile 8-oxoG modifications using RNA-immunoprecipitation and RNA sequencing (8-oxoG RIP-seq) to identify 343 RNA transcripts heavily enriched in oxidations in human bronchial epithelial BEAS-2B cell cultures exposed to 1 ppm formaldehyde for 2 h. RNA oxidation altered expression of many transcripts involved in chromatin modification and p53-mediated DNA-damage responses, two pathways that play key roles in sustaining genome integrity and typically deregulated in tumorigenesis. Given that these observations were identified in normal cells exhibiting minimal cell stress and death phenotypes (for example, lack of nuclear shrinkage, F-actin alterations or increased LDH activity); we hypothesize that oxidative modification of specific RNA transcripts following formaldehyde exposure denotes an early process occurring in carcinogenesis analogous to the oxidative events surfacing at early stages of neurodegenerative diseases. As such, we provide initial investigations of RNA oxidation as a potentially novel mechanism underlying formaldehyde-induced tumorigenesis.

Topics: Carcinogens; Cells, Cultured; DNA Damage; Formaldehyde; Guanine; Humans; Neurodegenerative Diseases; Oxidation-Reduction; RNA

8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.

Topics: Animals; Apoptosis Inducing Factor; Benzamides; Calpain; Cell Nucleus; Corpus Striatum; Dipeptides; DNA Breaks, Single-Stranded; DNA Glycosylases; DNA Repair; DNA, Mitochondrial; Guanine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Mitochondria; Motor Activity; Neurodegenerative Diseases; Nitro Compounds; Oxidative Stress; Phosphoric Monoester Hydrolases; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Propionates

Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease-like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In a complementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Corpus Striatum; Deoxyguanosine; DNA Damage; DNA Repair Enzymes; DNA, Complementary; Embryo, Mammalian; Fibroblasts; Guanine; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Nitro Compounds; Nuclear Proteins; Oxidation-Reduction; Oxidative Stress; Phosphoric Monoester Hydrolases; Propionates; Stem Cells

We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Astrocytes; Cell Count; Cell Death; Central Nervous System Diseases; Epilepsy; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Growth Substances; Guanine; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Interleukins; Kainic Acid; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Neurofibrillary Tangles; Staining and Labeling; Tyrosine