Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing

Hum Mol Genet. 2015 Feb 1;24(3):828-40. doi: 10.1093/hmg/ddu500. Epub 2014 Sep 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging, Premature / genetics
  • Aging, Premature / metabolism*
  • Aging, Premature / pathology
  • Animals
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • DNA-Binding Proteins / deficiency*
  • Disease Models, Animal
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Motor Neurons / pathology*
  • Mutation
  • Nuclear Proteins / deficiency*
  • Oxidative Stress
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Transcription, Genetic / drug effects*


  • Aptx protein, mouse
  • DNA-Binding Proteins
  • Nuclear Proteins
  • SOD1 protein, human
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Hydrogen Peroxide
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1