Our goal here is to determine whether changes in the formation or processing of oxidative DNA damage are associated with neurodegeneration and Alzheimers Disease (AD). It is our hypothesis that DNA repair systems play critical roles in responding to multiple types of acute and chronic cellular stress. We have identified a DNA damage response cascade leading from PARP1 to defected mitophagy. In the rare autosomal recessive disease Ataxia Telangiectasia (AT,) we documented increased PARylation, low NAD+ and mitochondrial dysfunction across multiple species. Importantly, treatment with NAD+ precursors that restored NAD levels reduced the severity of AT neuropathology, improved neuromuscular function, delayed memory loss and dramatically extended lifespan. Mechanistically, we ascribed the benefits to improvements in DNA repair and mitophagy. This work underscores the important linkage between DNA repair and mitochondrial function and further points to novel therapeutic interventions. We previously reported that loss of DNA repair in mice on an AD background develop earlier and more severe AD pathology. In those studies, we used DNA polymerase beta (PolB) heterozygous mice and the 3xTgAD model to make 3xTg/PolB(+/-) mice. PolB functions in base excision repair (BER) and BER is the primary repair pathway for oxidative stress. Our results have clearly shown that DNA repair is important for preserving neuronal function during aging and under pathological conditions. Neil1 is an important evolutionarily conserved DNA repair glycosylase that shows high expression in the brain. We previously demonstrated that Neil1-null mice had deficiencies in spatial memory, olfaction functions, and were less protected from ischemic reperfusion injury. Adult neurogenesis is important for neural plasticity and brain function. However, neuroinflammation is a common feature found in neurodegenerative disorders and neurogenesis can either be enhanced or inhibited by it. To investigate what role Neil1 may contribute to neurogenesis and neuroinflammation resolution after an acute stress (gamma irradiation IR), we used Neil1 null mice. We found that they have reduced neurogenesis and resolution of neuroinflammation following IR damage. Two weeks after IR treatment, Neil1-null mice still showed impaired stress responses. These results demonstrate that DNA repair plays a vital role in neurogenesis and further that the resolution of neuroinflammation following acute stress is delayed in DNA repair deficient animals. These findings have implications for individuals with suboptimal DNA repair capacities as they may suffer greater injury following traumatic events.
| 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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