Triggering of Bcl-2-related pathway is associated with apoptosis of photoreceptors in Rpe65-/- mouse model of Leber's Congenital Amaurosis
Triggering of Bcl-2-related pathway is associated with apoptosis of photoreceptors in Rpe65-/- mouse model of Leber's Congenital Amaurosis
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DOI：
10.1007/s10495-008-0180-2
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发表时间：
2008-03-01
期刊：
影响因子：
7.2
通讯作者：
Schorderet, Daniel F.
中科院分区：
文献类型：
--
作者：
Cottet, Sandra;Schorderet, Daniel F.
RPE65蛋白的突变以光感受器丧失为特征，尽管触发视网膜细胞死亡的分子途径在很大程度上仍未解决。Bcl2家族蛋白在视网膜退行性变中的作用仍存在争议。然而，在几种视网膜损伤模型中已经观察到了Bcl2相关蛋白的改变。特别是，Bax被认为在小鼠青光眼模型的凋亡途径中以及在视网膜脱离相关细胞死亡中发挥关键作用。我们证实了Bcl2相关信号通路参与了RPE65依赖的光感受器细胞在疾病发展过程中的凋亡。促凋亡的Baxα和β亚型在病变的视网膜中表达上调。这与抗凋亡的Bcl2的进行性减少有关，反映了随着疾病的进展，Bcl2/Bax的比例失衡。此外，在RPE65缺陷的视网膜中观察到Baxβ从胞浆到线粒体的特异性移位。这与光感受器细胞在4个月龄时开始丢失有关，并在疾病发展过程中进一步增加。综上所述，这些数据表明，Bcl2-凋亡通路在Leber‘s先天性黑色素病中起着关键作用。他们进一步强调了一种新的Bax依赖的细胞凋亡调控机制，该机制基于该蛋白特定异构体的调控表达和激活。
Mutations in RPE65 protein is characterized by the loss of photoreceptors, although the molecular pathways triggering retinal cell death remain largely unresolved. The role of the Bcl-2 family of proteins in retinal degeneration is still controversial. However, alteration in Bcl-2-related proteins has been observed in several models of retinal injury. In particular, Bax has been suggested to play a crucial role in apoptotic pathways in murine glaucoma model as well as in retinal detachment-associated cell death. We demonstrated that Bcl-2-related signaling pathway is involved in Rpe65-dependent apoptosis of photoreceptors during development of the disease. Pro-apoptotic Bax alpha and beta isoforms were upregulated in diseased retina. This was associated with a progressive reduction of anti-apoptotic Bcl-2, reflecting imbalanced Bcl-2/Bax ratio as the disease progresses. Moreover, specific translocation of Bax beta from cytosol to mitochondria was observed in Rpe65-deficient retina. This correlated with the initiation of photoreceptor cell loss at 4 months of age, and further increased during disease development. Altogether, these data suggest that Bcl-2-apoptotic pathway plays a crucial role in Leber's congenital amaurosis disease. They further highlight a new regulatory mechanism of Bax-dependent apoptosis based on regulated expression and activation of specific isoforms of this protein.