Kruman Inna I, Wersto Robert P, Cardozo-Pelaez Fernando, Smilenov Lubomir, Chan Sic L, Chrest Francis J, Emokpae Roland, Gorospe Myriam, Mattson Mark P
Research Resources Branch, Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Neuron. 2004 Feb 19;41(4):549-61. doi: 10.1016/s0896-6273(04)00017-0.
Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical component of the DNA damage response in postmitotic neurons. Different genotoxic compounds (etoposide, methotrexate, and homocysteine) induced apoptosis accompanied by cell cycle reentry of terminally differentiated cortical neurons. In contrast, apoptosis initiated by stimuli that do not target DNA (staurosporine and colchicine) did not initiate cell cycle activation. Suppression of the function of ataxia telangiectasia mutated (ATM), a proximal component of DNA damage-induced cell cycle checkpoint pathways, attenuated both apoptosis and cell cycle reentry triggered by DNA damage but did not change the fate of neurons exposed to staurosporine and colchicine. Our data suggest that cell cycle activation is a critical element of the DNA damage response of postmitotic neurons leading to apoptosis.
越来越多的证据表明，神经退行性变涉及有丝分裂后神经元中细胞周期机制的激活。然而，这些与细胞周期相关的事件在神经元凋亡中的目的仍不清楚。在此，我们检验了这样一个假说，即细胞周期激活是有丝分裂后神经元DNA损伤反应的关键组成部分。不同的基因毒性化合物（依托泊苷、甲氨蝶呤和同型半胱氨酸）诱导凋亡，并伴有终末分化的皮质神经元重新进入细胞周期。相比之下，由不靶向DNA的刺激（星形孢菌素和秋水仙碱）引发的凋亡并未启动细胞周期激活。共济失调毛细血管扩张症突变基因（ATM）是DNA损伤诱导的细胞周期检查点途径的近端成分，抑制其功能可减弱DNA损伤引发的凋亡和细胞周期重新进入，但不会改变暴露于星形孢菌素和秋水仙碱的神经元的命运。我们的数据表明，细胞周期激活是有丝分裂后神经元DNA损伤反应导致凋亡的关键因素。
