Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss
Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss
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DOI：
10.1111/j.1471-4159.2006.03648.x
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Xia, WM
中科院分区：
文献类型：
--
作者：
Campbell, WA;Yang, H;Xia, WM
γ -分泌酶裂解由早老素、早老素增强子（pen2）、nicastrin和Aph-1复合物介导，是生成淀粉样蛋白的最后蛋白水解步骤，在阿尔茨海默病患者的大脑和Notch细胞内结构域中发现，这对神经元的正常发育至关重要。在这里，我们采用斑马鱼模型来研究Pen-2在神经元存活中的作用。我们发现(i)使用反义morpholino敲除Pen-2导致胰岛1阳性神经元减少，（ii）缺乏Pen-2或其他γ分泌酶成分的胚胎中Notch信号减少，（iii）敲除Pen-2的胚胎中的神经元损失不是由于缺乏神经元前体细胞或细胞增殖，（iv）缺乏Pen-2导致整个动物大量凋亡，这可以通过同时敲除肿瘤抑制因子p53来抑制。(v)敲低Pen-2基因的胚胎中，胰岛1或乙酰化小管蛋白阳性神经元的丢失可以通过敲低p53来部分恢复。我们的研究结果表明，敲低Pen-2直接诱导p53依赖的凋亡通路，导致神经元损失，并提示Pen-2在促进神经元细胞存活和保护细胞凋亡中发挥重要作用。
gamma-Secretase cleavage, mediated by a complex of presenilin, presenilin enhancer (Pen-2), nicastrin, and Aph-1, is the final proteolytic step in generating amyloid beta protein found in brains of Alzheimer's disease patients and Notch intracellular domain critical for proper neuronal development. Here, we employ the zebrafish model to study the role of Pen-2 in neuronal survival. We found that (i) knockdown of Pen-2 using antisense morpholino led to a reduction of islet-1 positive neurons, (ii) Notch signaling was reduced in embryos lacking Pen-2 or other gamma-secretase components, (iii) neuronal loss in Pen-2 knockdown embryos is not as a result of a lack of neuronal precursor cells or cell proliferation, (iv) absence of Pen-2 caused massive apoptosis in the whole animal, which could be suppressed by simultaneous knockdown of the tumor suppressor p53, (v) loss of islet-1 or acetylated tubulin positive neurons in Pen-2 knockdown embryos could be partially rescued by knockdown of p53. Our results demonstrate that knockdown of Pen-2 directly induces a p53-dependent apoptotic pathway that contributes to neuronal loss and suggest that Pen-2 plays an important role in promoting neuronal cell survival and protecting from apoptosis in vivo.