Guo H, Pétrin D, Zhang Y, Bergeron C, Goodyer C G, LeBlanc A C
Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, Quebec, Canada.
Cell Death Differ. 2006 Feb;13(2):285-92. doi: 10.1038/sj.cdd.4401753.
Active caspase-6 (Csp-6) induces cell death in primary cultures of human neurons and is abundant in the neuropathological lesions of Alzheimer's disease. However, the mode of Csp-6 activation is not known. Here, we show that the Csp-1 inhibitor, Z-YVAD-fmk specifically prevents activation of Csp-6 and cell death in human neurons. A transient increase in Csp-1-like activity and an increase in the p23Csp-1 subunit occur early after serum deprivation. Recombinant active Csp-1 (R-Csp-1) cleaves recombinant and neuronal pro-Csp-6 in vitro resulting in Csp-6 activity. However, R-Csp-1 does not induce cell death when microinjected in human neurons despite the inhibition of serum-deprivation induced cell death with a Csp-1 dominant negative construct. These results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons. Furthermore, these results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death.
活性半胱天冬酶-6（Csp-6）可诱导原代人神经元细胞死亡，且在阿尔茨海默病的神经病理损伤中大量存在。然而，Csp-6的激活模式尚不清楚。在此，我们表明，半胱天冬酶-1（Csp-1）抑制剂Z-YVAD-fmk可特异性地阻止人神经元中Csp-6的激活及细胞死亡。血清剥夺后早期，Csp-1样活性短暂增加，且p23Csp-1亚基增加。重组活性Csp-1（R-Csp-1）在体外可切割重组及神经元前体Csp-6，从而产生Csp-6活性。然而，尽管用Csp-1显性负性构建体抑制了血清剥夺诱导的细胞死亡，但将R-Csp-1显微注射到人神经元中时并不会诱导细胞死亡。这些结果表明，Csp-1是原代人神经元中Csp-6介导的细胞死亡的上游正向调节因子。此外，这些结果表明，Csp-1的激活必须伴有凋亡刺激才能诱导Csp-6介导的细胞死亡。
