Our goal is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration observed after stroke, during aging or in 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). DNA repair declines with age and 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. Our recent results suggest that the Neil1 KO mice are more sensitive to stroke and generates more infarct area and recovers more slowly than wild type mice. In addition, using behavioral studies, we detected a memory deficiency in the Neil1 KO mice. Likewise, stroke recovery analysis in our Xrcc1 heterozygous mouse model revealed that even partial inactivation of the BER pathway was sufficient to confer less efficient recovery. With our prior work and these new results taken together, these findings underscore the importance of BER as a disease modifier especially to an acute stressor like stroke. AD is one of the leading causes of neurodegeneration 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 tested the hypothesis that a defect in DNA repair might exacerbate the AD phenotypes in a mouse model of Alzheimers disease (3xTg AD). Our results show that loss of DNA repair, even partially, is sufficient to increase cell death, mitochondrial dysfunction and diminish organismal learning in the 3xTgAD/PolBeta mouse model for Alzheimers disease. Loss of smelling is a common symptom reported in the elderly and as also as a consequence of neurodegeneration. There are multiple reasons why individuals loose their sense of smell with age and we are investigating how DNA repair impacts neurodegeneration as it relates to the olfaction. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair. Future research will aim to identify whether other DNA repair deficient animal models also share olfactory changes and whether DNA repair impacts the rate of loss of olfactory function.
| 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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