Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
J Neurochem. 2010 Oct;115(1):92-101. doi: 10.1111/j.1471-4159.2010.06909.x. Epub 2010 Jul 30.
Prolonged seizures activate members of the Bcl-2 homology domain 3-only sub-group of the Bcl-2 protein family, which are essential for initiation of apoptosis signaling. Bid is a potent pro-apoptotic Bcl-2 homology domain 3-only protein, which upon proteolytic activation translocates to mitochondria to promote activation of the Bax/Bak sub-group of the pro-apoptotic Bcl-2 family and thereby contributes to release of apoptogenic molecules, such as cytochrome c and possibly apoptosis-inducing factor (AIF). Bid-deficient mice have been reported to show reduced lesion volumes after ischemia and trauma in vivo but a causal role for Bid in the setting of seizure-induced neuronal death has not been investigated. In this study, we studied Bid activation following status epilepticus in mice and compared hippocampal damage between wild-type and Bid-deficient animals. Full-length Bid was detected in normal mouse hippocampus and the cleaved (activated) p15 fragment of Bid was detected shortly after status epilepticus. Bid-deficient mice underwent equivalent electrographic seizure responses during status epilepticus as wild-type animals. Hippocampal counts of degenerating neurons and surviving neuron-specific nuclear protein-positive cells were not significantly different between wild-type and Bid-deficient mice. Additionally, nuclear translocation of AIF was not reduced in Bid-deficient compared with wild-type animals subjected to status epilepticus. The present study demonstrates that AIF is not dependent on Bid for mitochondrial release and nuclear import in this model and that while Bid is cleaved during seizure-induced neuronal death, it may be functionally redundant or even not essential.
癫痫持续状态激活 Bcl-2 同源结构域 3 仅亚组的 Bcl-2 蛋白家族成员，这对于凋亡信号的启动至关重要。Bid 是一种有效的促凋亡 Bcl-2 同源结构域 3 仅蛋白，在蛋白水解激活后易位到线粒体，促进促凋亡 Bcl-2 家族 Bax/Bak 亚组的激活，从而有助于释放细胞色素 c 和可能的凋亡诱导因子 (AIF) 等促凋亡分子。据报道，Bid 缺陷小鼠在体内缺血和创伤后损伤体积减小，但 Bid 在癫痫发作诱导的神经元死亡中的因果作用尚未得到研究。在这项研究中，我们研究了癫痫持续状态后小鼠 Bid 的激活情况，并比较了野生型和 Bid 缺陷型动物海马区的损伤情况。在正常小鼠海马体中检测到全长 Bid，并且在癫痫持续状态后不久检测到 cleaved (激活的) p15 Bid 片段。Bid 缺陷型小鼠在癫痫持续状态期间经历了与野生型动物相当的电发作反应。野生型和 Bid 缺陷型小鼠之间的变性神经元计数和存活神经元特异性核蛋白阳性细胞没有显著差异。此外，在经历癫痫持续状态的 Bid 缺陷型与野生型动物中，AIF 的核易位没有减少。本研究表明，在该模型中，AIF 不依赖于 Bid 进行线粒体释放和核内输入，并且虽然 Bid 在癫痫发作诱导的神经元死亡过程中被切割，但它可能在功能上是冗余的，甚至是不必要的。
