Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons
Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons
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DOI：
10.1007/s10495-005-1681-x
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发表时间：
2005-12-01
期刊：
影响因子：
7.2
通讯作者：
Jacotot, E
中科院分区：
文献类型：
--
作者：
Chauvier, D;Lecoeur, H;Jacotot, E
在发育过程中以及在病理情况下，未能找到适当靶点或神经营养因子的神经元经历细胞死亡。使用原代皮质神经元进行急性血清剥夺（SD），我们已经研究了半胱天冬酶激活，线粒体功能障碍和细胞死亡参数。在一组代谢、信号传导和半胱天冬酶抑制剂中，只有那些能够干扰半胱天冬酶-2样活性的抑制剂保护原代神经元免受SID诱导的细胞死亡。原位检测和亚细胞分级显示胞浆caspase-2的非常早期的激活，其控制Bax裂解、再定位和线粒体膜透化（MMP）。z-VDVAD-fmk和对caspase-2特异性的SiRNA都消除了Bax变化、线粒体膜透化以及细胞色素c释放依赖性的caspase-9/caspase-3激活、核改变、磷脂酰丝氨酸暴露、神经突解体和神经元死亡。因此，胱天蛋白酶-2是一个早期的检查点，在原代神经元进行血清剥夺细胞凋亡的启动。
During development as well as in pathological situations, neurons that fail to find appropriate targets or neurotrophic factors undergo cell death. Using primary cortical neurons subjected to acute serum-deprivation (SD), we have examined caspases activation, mitochondrial dysfunction and cell death parameters. Among a panel of metabolic, signaling and caspases inhibitors only those able to interfere with caspase-2 like activity protect primary neurons against SID-induced cell death. In situ detection and subcellular fractionation demonstrate a very early activation of cytosolic caspase-2, which controls Bax cleavage, relocalization and mitochondrial membrane permeabilization (MMP). Both z-VDVAD-fmk and a siRNA specific for caspase-2 abolish Bax changes, mitochondrial membranes permeabilization, as well as cytochrome c release-dependent activation of caspase-9/caspase-3, nuclear alterations, phosphatidylserine exposure, neurites dismantling and neuronal death. Hence, caspase-2 is an early checkpoint for apoptosis initiation in primary neurons subjected to serum deprivation.