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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000723-06
Application #
8736598
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$427,351
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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
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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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