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 and 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. AD is one of the leading causes of neurodegeration and there are numerous documented cases of neurodegeneration associated with genetic DNA repair defects. Given that there is compelling evidence that DNA repair capacity alters the ability of mice to recover from an acute oxidative stress and that AD is associated with chronic oxidative stress. We wanted to test the hypothesis that a defect in DNA repair might exacerbate AD phenotypes in a mouse model (the 3xTg AD model). While the studies are still ongoing, there is preliminary evidence that suggests a defect in DNA repair capacity can modulate memory and learning. Full behavioural, memory and learning experiments are underway in mice to quantify the extent to which a DNA repair deficiency impacts the AD features.

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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Yang, Jenq-Lin; Lin, Yu-Ting; Chuang, Pei-Chin et al. (2014) BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1. Neuromolecular Med 16:161-74
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E et al. (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157:882-96
Canugovi, Chandrika; Shamanna, Raghavendra A; Croteau, Deborah L et al. (2014) Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease. Neurobiol Aging 35:1293-300
Sykora, Peter; Yang, Jenq-Lin; Ferrarelli, Leslie K et al. (2013) Modulation of DNA base excision repair during neuronal differentiation. Neurobiol Aging 34:1717-27
Rasmussen, Lene Juel; Shiloh, Yosef; Bergersen, Linda H et al. (2013) DNA damage response, bioenergetics, and neurological disease: The challenge of maintaining brain health in an aging human population. Mech Ageing Dev :
Maynard, Scott; Schurman, Shepherd H; Harboe, Charlotte et al. (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2-10
Wilson 3rd, David M; Bohr, Vilhelm A; McKinnon, Peter J (2008) DNA damage, DNA repair, ageing and age-related disease. Mech Ageing Dev 129:349-52
Fried, Linda P; Varadhan, Ravi; Bohr, Vilhelm A (2008) Opinion section on frailty. Mech Ageing Dev 129:665
Yang, Jenq-Lin; Weissman, Lior; Bohr, Vilhelm A et al. (2008) Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 7:1110-20