title: Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage.
abstract: The detailed mechanisms of prion-induced neurotoxicity are largely unknown. Here, we have studied the role of DNA damage caused by reactive oxygen species in a mouse scrapie model by characterizing prion disease in the ogg1(-/-)mutyh(-/-) double knockout, which is compromised in oxidative DNA base excision repair. Ogg1 initiates removal of the major oxidation product 8-oxoguanine (8-oxoG) in DNA, and Mutyh initiates removal of adenine that has been misincorporated opposite 8-oxoG. Our data show that the onset of clinical signs appeared unaffected by Mutyh and Ogg1 expression. However, the ogg1(-/-)mutyh(-/-) mice displayed a significantly shorter clinical phase of the disease. Thus, accumulation of oxidative DNA damage might be of particular importance in the terminal clinical phase of prion disease. The prion-induced pathology and lesion profile were similar between knockout mice and controls. The fragmentation pattern of protease-resistant PrP as revealed in Western blots was also identical between the groups. Our data show that the fundamentals of prion propagation and pathological manifestation are not influenced by the oxidative DNA damage repair mechanisms studied here, but that progressive accumulation of oxidative lesions may accelerate the final toxic phase of prion disease.
authors.affiliation: Norwegian School of Veterinary Science, NO-0033 Oslo, Norway.
authors.forename: Clara M O
authors.initials: CM
authors.lastname: Jalland
authors.affiliation: Norwegian Veterinary Institute, Oslo, Norway.
authors.forename: Sylvie L
authors.initials: SL
authors.lastname: Benestad
authors.affiliation: Norwegian School of Veterinary Science, NO-0033 Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Ersdal
authors.affiliation: Department of Medical Biochemistry and Oslo University Hospital, University of Oslo, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Department of Microbiology, Oslo University Hospital, University of Oslo, Norway.
authors.forename: Rajikala
authors.initials: R
authors.lastname: Suganthan
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Department of Medical Biochemistry and Oslo University Hospital, University of Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Department of Microbiology, Oslo University Hospital, University of Oslo, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Norwegian School of Veterinary Science, NO-0033 Oslo, Norway. Electronic address: Michael.Tranulis@nvh.no.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tranulis
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004195:Disease Models, Animal; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species; D012608:Scrapie / Q000235:genetics* / Q000473:pathology
chemical_list: D011328:Prions; D017382:Reactive Oxygen Species; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
keywords: DNA damage; DNA repair; Free radicals; Neurodegeneration; Prion disease; Reactive oxygen species