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.
| Hou, Yujun; Lautrup, Sofie; Cordonnier, Stephanie et al. (2018) NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115:E1876-E1885 |
| Baptiste, Beverly A; Katchur, Steven R; Fivenson, Elayne M et al. (2018) Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention. Free Radic Biol Med 124:149-162 |
| Fivenson, Elayne M; Lautrup, Sofie; Sun, Nuo et al. (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202-209 |
| Kerr, Jesse S; Adriaanse, Bryan A; Greig, Nigel H et al. (2017) Mitophagy and Alzheimer's Disease: Cellular and Molecular Mechanisms. Trends Neurosci 40:151-166 |
| Fang, Evandro F; Lautrup, Sofie; Hou, Yujun et al. (2017) NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med 23:899-916 |
| Fang, Evandro F; Bohr, Vilhelm A (2017) NAD(+): The convergence of DNA repair and mitophagy. Autophagy 13:442-443 |
| Croteau, Deborah L; Fang, Evandro Fei; Nilsen, Hilde et al. (2017) NAD(+) in DNA repair and mitochondrial maintenance. Cell Cycle 16:491-492 |
| Misiak, Magdalena; Vergara Greeno, Rebeca; Baptiste, Beverly A et al. (2017) DNA polymerase ? decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease. Aging Cell 16:162-172 |
| Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2017) Genome instability in Alzheimer disease. Mech Ageing Dev 161:83-94 |
| Karikkineth, Ajoy C; Scheibye-Knudsen, Morten; Fivenson, Elayne et al. (2017) Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev 33:3-17 |
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