We are testing the hypothesis that the accumulation of oxidative DNA damage contributes to neuronal dysfunction seen in neurodegenerative diseases by utilizing multiple model systems like transgenic mice, cultured cells and C. elegans. We are focusing on Alzheimer's disease (AD) since this is the most prevalent form of dementia in people 65 years or older. The base excision repair (BER) pathway repairs oxidative DNA damage, such as base modifications, which occur spontaneously or from attack by reactive oxygen species (ROS). DNA polymerase Beta (PolB) is responsible for the DNA synthesis step in the BER pathway, which can be rate limiting. Previously we bred the 3xTg AD mouse to our DNA Polymerase Beta heterozygous mouse (PolB) to create a new mouse model, 3xTgAD/PolB+/- that displayed several important new features that the parental AD mouse model did not. We observed elevated cell death markers, altered ABeta deposition, greater mitochondrial dysfunction, worse memory and learning and worse smelling defects. These added features make the new mouse model more similar to the AD presentation seen in humans. Together, our work and others suggest that deficiencies in BER enzymes might contribute to the accumulation of oxidative damage in both nuclear and mitochondria DNA of AD patients and contribute to disease progression. As a consequence of increased DNA damage we propose and are testing whether there is also increased parylation by Poly(ADP)ribose polymerases which consumes nicotinamide adenine dinucleotide (NAD). We are testing whether supplementation of AD mouse models with various forms of NAD precursors improves 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 |
| 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 |
| Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2017) Genome instability in Alzheimer disease. Mech Ageing Dev 161:83-94 |
| Desler, Claus; Frederiksen, Jane H; Angleys, Maria et al. (2015) Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline. Mitochondrion 25:34-7 |
| Bürkle, Alexander; Grune, Tilman; Gonos, Efstathios S et al. (2015) Editorial. Mech Ageing Dev 151:1 |
| Sykora, Peter; Misiak, Magdalena; Wang, Yue et al. (2015) DNA polymerase ? deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43:943-59 |
| Maynard, Scott; Hejl, Anne-Mette; Dinh, Thuan-Son T et al. (2015) Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer's disease patients. Aging (Albany NY) 7:793-815 |
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