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- Title
Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing
- Authors
Carroll, Jean; Page, Tristan K.W.; Shih-Chieh Chiang; Kalmar, Bernadett; Bode, David; Greensmith, Linda; Mckinnon, Peter J; Thorpe, Julian R.; Hafezparast, Majid; El-Khamisy, Sherif F.
- Abstract
Aprataxin (APTX) deficiencycausesprogressive cerebellardegeneration, ataxiaandoculomotor apraxia inman. Cell free assaysandcrystal structure studiesdemonstrate a role forAPTXin 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 (SOD1G93A) is expressed in an Aptx2/2 mouse strain. We report a delayed population doubling and accelerated senescence in Aptx2/2 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 SOD1G93A 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.
- Publication
Human Molecular Genetics, 2015, Vol 24, Issue 3, p828
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu500