Our goal in this project is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration observed after stroke or in aging and age-associated diseases. Stroke is a leading cause of death, and ROS generated during ischemia may contribute to neuronal death. Although stroke is treatable with timely medical help, only 10% of stroke victims recover completely from a major stroke episode. Thus, it is important not only to identify risk factors for stroke, but to identify factors that influence post-stroke outcomes (i.e., reduce disability or death from stroke). It has been proposed that lower BER capacity could partly explain the increased incidence and adverse effects of stroke in older individuals. Therefore, we are investigating the impact of simulated stroke in mice carrying defects in specific DNA glycosylases or other BER enzymes. We are testing the hypothesis that loss of BER capacity negatively impacts the brains ability to recover from acute oxidative stress experienced during a stroke. Using the Ogg1 knockout mice and a stroke model, we previously demonstrated that Ogg1 KO animals had larger infarct volumes and displayed poor recovery following stroke. Our very recent results suggest that the Neil1 KO mice are more sensitive to stroke and generates more ischemia and recovers more slowly than wild type mice. In addition, using behavioral studies, we detected a memory deficiency in the Neil1 KO mice. This work suggests that a BER deficiency may be directly associated with cognitive function and we plan to extend these studies to other DNA repair defective mouse models on another genetic background. Together, these findings underscore the importance of BER as a disease modifier. In other studies, we have studied DNA repair in individual primary rat neurons. These neurons repair many kinds of DNA damage, and it is particularly novel that they repair UV induced DNA damage. This is important because UV damage to DNA is removed by the DNA repair process called nucleotide excision repair, which is generally thought to be deficient in the CNS. We also find attenuation of oxidative DNA damage repair in differentiating neurons and we find that the DNA repair in the synaptic region is quite robust after oxidative stress. Furthermore, there seems to be a connection between neurotransmission and DNA repair because the addition of neurotransmitters to neurons increases DNA damage and repair. Specifically, we observed that non-toxic physiological levels of glutamate induced DNA damage and this damage was dependent upon calcium and mitochondrial ROS because calcium chelators and mitochondrial inhibitors prevented the DNA damage. We further showed that the glutamate-induced DNA damage induced APE1 mRNA and that APE1 is a key player in the repair of glutamate-induced DNA damage. The APE1 induction was shown to be dependent on signaling through a calcium and CREB-mediated pathway. Given that glutamate is the most abundant neurotransmitter, this raises the notion that there exists a connection between DNA damage, repair, memory and learning. There are numerous documented cases of neurodegeneration associated with genetic DNA repair defects. More recently mouse models have focused our attention on the correlation between neurodegeneration and mitochondrial DNA repair maintenance and repair. With this focus in mind, we have investigated the cellular localization and brain distribution patterns for Aprataxin (APTX), the protein deficient in ataxia with oculomotor apraxia (AOA1). APTX, together with TDP1, constitute a class of DNA repair enzymes that modify DNA ends prior to ligation. We were the first to report that an isoform of APTX is localized to mitochondria and that this isoform is expression in the cerebellum. Additionally, we showed that acute depletion of APTX in human cells caused mitochondrial dysfunction. Our results support the proposal that altered mitochondrial DNA repair may contribute, in part, to neurodegeneration see in AOA1 patients. These experiments and others are illuminating the in vivo role for BER enzymes and highlighting how BER deficiencies might impinge on human health.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Fang, Evandro Fei; Scheibye-Knudsen, Morten; Chua, Katrin F et al. (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308-21
Cheng, Aiwu; Yang, Ying; Zhou, Ye et al. (2016) Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. Cell Metab 23:128-42
Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2016) Genome instability in Alzheimer disease. Mech Ageing Dev :
Maynard, Scott; Fang, Evandro Fei; Scheibye-Knudsen, Morten et al. (2015) DNA Damage, DNA Repair, Aging, and Neurodegeneration. Cold Spring Harb Perspect Med 5:
Akbari, Mansour; Sykora, Peter; Bohr, Vilhelm A (2015) Slow mitochondrial repair of 5'-AMP renders mtDNA susceptible to damage in APTX deficient cells. Sci Rep 5:12876
Desler, Claus; Frederiksen, Jane H; Angleys, Maria et al. (2015) Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline. Mitochondrion 25:34-7
Akbari, Mansour; Morevati, Marya; Croteau, Deborah et al. (2015) The role of DNA base excision repair in brain homeostasis and disease. DNA Repair (Amst) 32:172-9
Maynard, Scott; Hejl, Anne-Mette; Dinh, Thuan-Son T et al. (2015) Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer's disease patients. Aging (Albany NY) 7:793-815
Sykora, Peter; Misiak, Magdalena; Wang, Yue et al. (2015) DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43:943-59
Ghosh, Somnath; Canugovi, Chandrika; Yoon, Jeong Seon et al. (2015) Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice. Neurobiol Aging 36:2319-30

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