Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.
Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.
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DOI：
10.1093/hmg/ddu500
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发表时间：
2015-02-01
影响因子：
3.5
通讯作者：
El-Khamisy SF
中科院分区：
文献类型：
--
作者：
Carroll J;Page TK;Chiang SC;Kalmar B;Bode D;Greensmith L;Mckinnon PJ;Thorpe JR;Hafezparast M;El-Khamisy SF
Aprataxin（APTX）缺乏可导致人类进行性小脑变性、共济失调和眼用不能，无细胞实验和晶体结构研究表明APTX在解决5′-腺苷酸核酸断裂中发挥作用，但由于缺乏合适的模型系统，APTX在脊椎动物中的功能尚不清楚。在这里，我们生成了一个小鼠模型，其中超氧化物歧化酶1（SOD 1G 93 A）的致病突变体在Aptx−/−小鼠品系中表达。我们报告了Aptx−/−原代小鼠成纤维细胞延迟的群体倍增和加速衰老，这不是由于可检测到的端粒不稳定性或细胞周期失调，而是与氧化应激后转录恢复减少有关。SOD 1G 93 A的表达揭示了体外培养细胞和体内缺乏Aptx的组织中的存活缺陷。存活的神经元具有大量且深的核被膜内陷，这是细胞应激的标志。此外，它们具有增加的高密度核区域数量和伴随的组蛋白H3 K9三甲基化增加，这是沉默染色质的标志。最后，在生物体水平上也观察到加速的细胞衰老，如胰岛素样生长因子1（IGF-1）的下调所示，这是过早衰老的标志。总之，这项研究证明了Aptx在体内的保护作用，并表明其损失导致神经系统中DNA断裂的进行性积累，引发系统性过早衰老的标志。
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 (SOD1G93A) 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 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.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5.3
作者：
Cassina, Patricia;Cassina, Adriana;Radi, Rafael
通讯作者：
Radi, Rafael
影响因子：
30.8
作者：
Date, H;Onodera, O;Tsuji, S
通讯作者：
Tsuji, S
影响因子：
4.3
作者：
Chiang, Shih-Chieh;Carroll, Jean;El-Khamisy, Sherif F.
通讯作者：
El-Khamisy, Sherif F.
影响因子：
3.1
作者：
Lev, Nirit;Ickowicz, Debby;Offen, Daniel
通讯作者：
Offen, Daniel