Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma
Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma
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DOI：
10.1096/fj.09-145870
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发表时间：
2010-03-01
期刊：
影响因子：
4.8
通讯作者：
Henshall, David C.
中科院分区：
文献类型：
--
作者：
Engel, Tobias;Murphy, Brona M.;Henshall, David C.
神经元死亡对癫痫发病机制的功能意义及其潜在的分子机制仍不完全清楚。 p53转录因子与癫痫损伤有关，但其靶基因以及其控制下的细胞死亡对癫痫发展的影响尚不清楚。在本研究中，我们报道了小鼠杏仁核内红藻氨酸引发的癫痫持续状态（SE）导致 p53 快速积累和随后的海马损伤。 p53 上调的凋亡介质 (Puma)（一种受 p53 控制的促凋亡 Bcl-2 同源结构域 3 蛋白）的表达在 SE 几小时内增加。 Puma 的诱导被 p53 的药理学抑制所阻断，海马损伤也减少。在患有 SE 的 p53 缺陷小鼠中，Puma 诱导也被阻断。与表达 Puma 的小鼠相比，SE 后 Puma 缺陷小鼠的海马损伤明显更小。长期、连续遥测脑电图监测显示，与表达 Puma 的小鼠相比，Puma 缺陷小鼠的癫痫发作频率减少了 60%。这些是第一个数据显示促凋亡蛋白的基因缺失会急剧影响神经元死亡，随后从长远来看会改变癫痫的表型，支持凋亡途径激活是癫痫发生的触发因素的概念。-Engel, T., Murphy, B. M., Hatazaki, S., Jimenez-Mateos, E. M., Concannon, C. G., Woods, I.，Prehn，J. H. M.，Henshall，D. C. 缺乏促凋亡 Puma 的小鼠癫痫持续状态后减少海马损伤和癫痫发作。 FASEB J. 24, 853-861 (2010)。 www.fasebj.org
The functional significance of neuronal death for pathogenesis of epilepsy and the underlying molecular mechanisms thereof remain incompletely understood. The p53 transcription factor has been implicated in seizure damage, but its target genes and the influence of cell death under its control on epilepsy development are unknown. In the present study, we report that status epilepticus (SE) triggered by intra-amygdala kainic acid in mice causes rapid p53 accumulation and subsequent hippocampal damage. Expression of p53-up-regulated mediator of apoptosis (Puma), a proapoptotic Bcl-2 homology domain 3-only protein under p53 control, was increased within a few hours of SE. Induction of Puma was blocked by pharmacologic inhibition of p53, and hippocampal damage was also reduced. Puma induction was also blocked in p53-deficient mice subject to SE. Compared to Puma-expressing mice, Puma-deficient mice had significantly smaller hippocampal lesions after SE. Long-term, continuous telemetric EEG monitoring revealed a similar to 60% reduction in the frequency of epileptic seizures in the Puma-deficient mice compared to Puma-expressing mice. These are the first data showing genetic deletion of a proapoptotic protein acting acutely to influence neuronal death subsequently alters the phenotype of epilepsy in the long-term, supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis.-Engel, T., Murphy, B. M., Hatazaki, S., Jimenez-Mateos, E. M., Concannon, C. G., Woods, I., Prehn, J. H. M., Henshall, D. C. Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma. FASEB J. 24, 853-861 (2010). www.fasebj.org