title: Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.
abstract: Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically.
authors.affiliation: Genome Damage and Stability Center, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Carroll
authors.affiliation: School of Life Science, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Tristan K W
authors.initials: TK
authors.lastname: Page
authors.affiliation: Department of Molecular Biology and Biotechnology, Krebs Institute, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.affiliation: School of Life Science, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bode
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mckinnon
authors.affiliation: School of Life Science, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Thorpe
authors.affiliation: School of Life Science, University of Sussex, Brighton BN1 9QG, UK s.el-khamisy@sheffield.ac.uk m.hafezparast@sussex.ac.uk.
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
authors.affiliation: Genome Damage and Stability Center, University of Sussex, Brighton BN1 9RQ, UK Department of Molecular Biology and Biotechnology, Krebs Institute, University of Sheffield, Sheffield S10 2TN, UK Center of Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt s.el-khamisy@sheffield.ac.uk m.hafezparast@sussex.ac.uk.
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C514665:Aptx protein, mouse; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606290:SOD1 protein, human; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1