Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways.
Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways.
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DOI：
10.1016/j.expneurol.2009.04.032
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Vosler, Peter S.;Sun, Dandan;Wang, Suping;Gao, Yanqin;Kintner, Douglas B.;Signore, Armando P.;Cao, Guodong;Chen, Jun
最近的发现表明，caspase非依赖的细胞死亡途径是神经退行性疾病中普遍存在的一种机制，而凋亡诱导因子(AIF)是这种神经元死亡模式的重要效应因子。目前已知的兴奋性应激后AIF释放的机制有两种，即PARP-1和calain。为了测试PARP-1和calain在触发AIF释放方面是否存在相互作用，我们使用了大鼠原代皮质神经元的NMDA毒性模型。暴露于NMDA可导致AIF截断和核移位，shRNA介导的AIF下调可起到神经保护作用。Calain和PARP-1都参与了AIF的处理，因为AIF被截断，核移位和神经元死亡都可以通过腺相关病毒介导的Calain抑制、内源性CalPasatin的过表达或PARP-1抑制剂3-ABA的处理来减轻。由于PARP-1的抑制作用阻止了线粒体Calain的激活，因此PARP-1的激活是Calain激活所必需的。最后，NMDA毒性以PARP-1依赖的方式诱导线粒体钙离子失衡。因此，PARP-1通过PARP-1诱导的线粒体钙稳态的改变与线粒体钙蛋白酶的激活联系在一起。总而言之，这些发现将触发AIF诱导神经元死亡的两个看似独立的机制联系在一起。
Recent discoveries show that caspase-independent cell death pathways are a pervasive mechanism in neurodegenerative diseases, and apoptosis-inducing factor (AIF) is an important effector of this mode of neuronal death. There are currently two known mechanisms underlying AIF release following excitotoxic stress, PARP-1 and calpain. To test whether there is an interaction between PARP-1 and calpain in triggering AIF release, we used the NMDA toxicity model in rat primary cortical neurons. Exposure to NMDA resulted in AIF truncation and nuclear translocation, and shRNA-mediated knock down of AIF resulted in neuroprotection. Both calpain and PARP-1 are involved with AIF processing as AIF truncation, nuclear translocation and neuronal death were attenuated by calpain inhibition using adeno-associated virus-mediated overexpression of the endogenous calpain inhibitor, calpastatin, or treatment with the PARP-1 inhibitor 3-ABA. Activation of PARP-1 is necessary for calpain activation as PARP-1 inhibition blocked mitochondrial calpain activation. Finally, NMDA toxicity induces mitochondrial Ca2+ dysregulation in a PARP-1 dependent manner. Thus, PARP-1 and mitochondrial calpain activation are linked via PARP-1-induced alterations in mitochondrial Ca2+ homeostasis. Collectively, these findings link the two seemingly independent mechanisms triggering AIF-induced neuronal death.
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影响因子：
11.4
作者：
Cheung, Eric C. C.;Joza, Nicholas;Slack, Ruth S.
通讯作者：
Slack, Ruth S.
影响因子：
5.5
作者：
Duan, Yuntao;Gross, Robert A.;Sheu, Shey-Shing
通讯作者：
Sheu, Shey-Shing
影响因子：
5.3
作者：
Marks, JD;Boriboun, C;Wang, J
通讯作者：
Wang, J
影响因子：
11.2
作者：
Urushitani, M;Shimohama, S;Kimura, J
通讯作者：
Kimura, J
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.