Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions and posttranslational modifications. We and others identified several protein interactions for the core BER enzymes. Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions, which create bursts of oxidative damage. Thus we are exploring mechanisms to stimulate DNA repair pathways since we believe elevated DNA repair capacity may thwart cell death and improve cellular metabolism and could limit age associated degeneration. Brain cells have particularly high basal levels of metabolic activity and use oxidative damage repair mechanisms to remove oxidative damage from DNA and dNTP pools and nevertheless DNA damage accrues with normal aging. Accumulating DNA damage and loss of robust DNA repair pathways with age may contribute to neurological dysfunction. In part, neurodegeneration may arise in individuals that lack BER DNA repair because in non-proliferating cells it is essential and disruption of these processes impact mitochondrial fitness which in turn compromises cellular energetics and cell survival. Recently, we found that loss of DNA glycosylase endonuclease 8-like 1 (NEIL1) in mice causes deficits in spatial memory retention. Furthermore, we found that there is a significant loss of NEIL1 enzyme levels and its activity in postmortem Alzheimer's disease brains. Interestingly, the expression levels of Neil1 messenger RNA are higher in the olfactory bulb compared with other areas of the brain. Olfaction in mice is a central brain function that involves many central nervous system pathways. Thus, we studied the effect of complete loss of Neil1 gene on olfactory function. We explored olfactory function in mice with 3 different behavioral tests namely, olfactory sensitivity, performance, and buried food tests. Neil1 KO mice performed poorly compared with wild-type mice in all 3 tests. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair. Changes in olfactory are often seen early in the development of AD and other neurodegenerative conditions, therefore we are pursuing whether our other DNA repair deficient mouse model also possess olfactory functional deficits. Elucidation of mechanism that contributes to olfactory degeneration may have particular relevance for many neurodegenerative diseases including Alzheimer's and Parkinsons disease.
| Fang, Evandro Fei; Froetscher, Lynn; Scheibye-Knudsen, Morten et al. (2018) Emerging antitumor activities of the bitter melon (Momordica charantia). Curr Protein Pept Sci : |
| 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 |
| Rahnasto-Rilla, Minna K; McLoughlin, Padraig; Kulikowicz, Tomasz et al. (2017) The Identification of a SIRT6 Activator from Brown Algae Fucus distichus. Mar Drugs 15: |
| Fang, Evandro F; Bohr, Vilhelm A (2017) NAD(+): The convergence of DNA repair and mitophagy. Autophagy 13:442-443 |
| Fakouri, Nima Borhan; Durhuus, Jon Ambæk; Regnell, Christine Elisabeth et al. (2017) Rev1 contributes to proper mitochondrial function via the PARP-NAD+-SIRT1-PGC1? axis. Sci Rep 7:12480 |
| 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 |
| Van Meter, Michael; Simon, Matthew; Tombline, Gregory et al. (2016) JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep 16:2641-2650 |
| Fang, Evandro Fei; Kassahun, Henok; Croteau, Deborah L et al. (2016) NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab 24:566-581 |
| Nygaard, Rie Harboe; Maynard, Scott; Schjerling, Peter et al. (2016) Acquired Localized Cutis Laxa due to Increased Elastin Turnover. Case Rep Dermatol 8:42-51 |
Showing the most recent 10 out of 78 publications
