title: Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior.
abstract: Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKIIalpha-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration.
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: Olve
authors.initials: O
authors.lastname: Moldestad
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.forename: Harald
authors.initials: H
authors.lastname: Carlsen
authors.forename: Gaute
authors.initials: G
authors.lastname: Nesse
authors.forename: Johan F
authors.initials: JF
authors.lastname: Storm
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Mansuy
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
mesh_terms: D000818:Animals; D001007:Anxiety / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D001522:Behavior, Animal / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000633:toxicity*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D050505:Mutant Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D016548:Prosencephalon / Q000187:drug effects* / Q000473:pathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D051981:Uracil-DNA Glycosidase / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D050505:Mutant Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051981:Uracil-DNA Glycosidase