Hitomi Junichi, Katayama Taiichi, Taniguchi Manabu, Honda Akiko, Imaizumi Kazunori, Tohyama Masaya
Department of Anatomy and Neuroscience, Osaka University Medical School, Japan.
Neurosci Lett. 2004 Mar 4;357(2):127-30. doi: 10.1016/j.neulet.2003.12.080.
Recently, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal death in patients with Alzheimer's disease. Treatment of human neuroblastoma cells with ER stress inducers causes apoptotic death. We confirmed that ER stress inducers specifically targeted the ER to cause apoptotic morphological changes. We also found that caspase-3, and not caspase-9 (a known mitochondrial apoptotic mediator), was mainly activated by ER stress. We generated the neuroblastoma cells that stably expressed caspase-12 and analyzed its influence on caspase-3 activation and vulnerability to ER stress. Cells expressing caspase-12 were more vulnerable to ER stress than cells expressing the empty vector, concomitant with increased activation of caspase-3. These findings suggested that activation of ER-resident caspase-12 indirectly activates cytoplasmic caspase-3 and might be important in ER stress-induced neuronal apoptosis.
最近，内质网（ER）功能障碍被认为与阿尔茨海默病患者的神经元死亡有关。用内质网应激诱导剂处理人神经母细胞瘤细胞会导致凋亡性死亡。我们证实内质网应激诱导剂特异性地靶向内质网，从而引起凋亡形态学变化。我们还发现，主要是caspase-3而非caspase-9（一种已知的线粒体凋亡介质）被内质网应激激活。我们构建了稳定表达caspase-12的神经母细胞瘤细胞，并分析了其对caspase-3激活和内质网应激易感性的影响。与表达空载体的细胞相比，表达caspase-12的细胞对内质网应激更敏感，同时caspase-3的激活增加。这些发现表明，内质网驻留的caspase-12的激活间接激活细胞质中的caspase-3，并且可能在内质网应激诱导的神经元凋亡中起重要作用。
