title: Modeling the impact of mitochondrial DNA damage in forebrain neurons and beyond.
abstract: We have generated an inducible transgenic mouse model, which expresses a mutated version of UNG1 (mutUNG1) that removes thymine, in addition to uracil from mitochondrial DNA. The abasic-sites (AP-sites) generated by removal of thymine or uracil are a threat to genomic integrity, and are particularly harmful in mitochondria due to inhibition of mitochondrial DNA polymerase. MutUNG1, accompanied by a luciferase reporter-gene, is controlled by the Tet-on system. Transgene expression is spatially regulated by the forebrain specific CaMKIIα-promoter, and temporally by the addition of doxycycline. Mice harboring this transgene develop compromised mitochondrial dynamics, neurodegeneration and impaired behavior.
authors.affiliation: Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, Oslo University Hospital and University of Oslo, NO-0027 Oslo, Norway.
authors.forename: Knut H
authors.initials: KH
authors.lastname: Lauritzen
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.forename: Johan F
authors.initials: JF
authors.lastname: Storm
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
mesh_terms: D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D054629:Genome, Mitochondrial / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C501505:Ing1 protein, mouse; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D004259:DNA-Directed DNA Polymerase