ArticleHuman molecular genetics2015
Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 17 citations in OpenAlex.
- Induced pluripotent stem cells carrying novel APTX mutations presented defective neural differentiation with the accumulation of DNA single-strand breaks.Cell death discovery · 2025Article
- Avian Lifespan Network Reveals Shared Mechanisms and New Key Players in Animal Longevity.Aging cell · 2025Article
- Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.Translational neurodegeneration · 2023Review
- SMN-deficient cells exhibit increased ribosomal DNA damage.Life science alliance · 2022Article
- DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity.Cellular and molecular life sciences : CMLS · 2021Review
- Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis.Journal of clinical medicine · 2019Article
- Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.The EMBO journal · 2018Article
- DNA plasticity and damage in amyotrophic lateral sclerosis.Neural regeneration research · 2018Review
- Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical-induced DNA damage.Science advances · 2017Article
- Article
- Neurological disorders associated with DNA strand-break processing enzymes.Mechanisms of ageing and development · 2017Review
- Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease.Immunology · 2016Review
- Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease.Progress in biophysics and molecular biology · 2015Review
- Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan.Molecular cancer therapeutics · 2015Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
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.
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