title: Neil3 induced neurogenesis protects against prion disease during the clinical phase.
abstract: Base excision repair (BER) is the major pathway for repair of oxidative DNA damage. Mice with genetic knockout of the BER enzyme Neil3 display compromised neurogenesis in the sub-ventricular zone of the lateral ventricle and sub-granular layer of the dentate gyrus of the hippocampus. To elucidate the impact of oxidative DNA damage-induced neurogenesis on prion disease we applied the experimental prion disease model on Neil3-deficient mice. The incubation period for the disease was similar in both wild type and Neil3-/-mice and the overall neuropathology appeared unaffected by Neil3 function. However, disease in the Neil3-/-mice was of shorter clinical duration. We observed a mildly reduced astrogliosis in the hippocampus and striatum in the Neil3-deficient mice. Brain expression levels of neuronal progenitor markers, nestin (Nestin), sex determining region Box 2 (Sox2), Class III beta-tubulin (Tuj1) decreased towards end-stage prion disease whereas doublecortin (Dcx) levels were less affected. Neuronal nuclei (NeuN), a marker for mature neurons declined during prion disease and more pronounced in the Neil3-/-group. Microglial activation was prominent and appeared unaffected by loss of Neil3. Our data suggest that neurogenesis induced by Neil3 repair of oxidative DNA damage protects against prion disease during the clinical phase.
authors.affiliation: Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Campus Adamstuen Oslo, Norway.
authors.forename: Clara M O
authors.initials: CM
authors.lastname: Jalland
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Microbiology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Norwegian Veterinary Institute, Oslo, Norway.
authors.forename: Sylvie L
authors.initials: SL
authors.lastname: Benestad
authors.affiliation: Norwegian Veterinary Institute, Oslo, Norway.
authors.forename: Torfinn
authors.initials: T
authors.lastname: Moldal
authors.affiliation: Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Campus Adamstuen Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Ersdal
authors.affiliation: Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Campus Adamstuen Oslo, Norway.
authors.forename: Gjermund
authors.initials: G
authors.lastname: Gunnes
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Rajikala
authors.initials: R
authors.lastname: Suganthan
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Microbiology, Oslo University Hospital and University of Oslo, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Norwegian University of Life Sciences, Faculty of Veterinary Medicine and Biosciences, Campus Adamstuen Oslo, Norway.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tranulis
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004249:DNA Damage; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D055786:Gene Knockout Techniques; D020547:Lateral Ventricles / Q000378:metabolism; D008297:Male; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000235:genetics* / Q000378:metabolism; D055495:Neurogenesis; D018384:Oxidative Stress; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human