Cottet Sandra, Schorderet Daniel F
Institute for Research in Ophthalmology (IRO), Avenue Grand-Champsec 64, 1950, Sion 4, Switzerland.
Apoptosis. 2008 Mar;13(3):329-42. doi: 10.1007/s10495-008-0180-2.
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.
RPE65蛋白的突变特征是光感受器丧失，尽管触发视网膜细胞死亡的分子途径在很大程度上仍未明确。Bcl-2蛋白家族在视网膜变性中的作用仍存在争议。然而，在几种视网膜损伤模型中已观察到Bcl-2相关蛋白的改变。特别是，有人提出Bax在小鼠青光眼模型以及视网膜脱离相关的细胞死亡的凋亡途径中起关键作用。我们证明，在疾病发展过程中，Bcl-2相关信号通路参与了Rpe65依赖的光感受器凋亡。促凋亡的Baxα和β亚型在患病视网膜中上调。这与抗凋亡的Bcl-2的逐渐减少有关，反映出随着疾病进展Bcl-2/Bax比值失衡。此外，在Rpe65缺陷型视网膜中观察到Baxβ从细胞质到线粒体的特异性易位。这与4个月大时光感受器细胞丧失的开始相关，并在疾病发展过程中进一步增加。总之，这些数据表明Bcl-2凋亡途径在莱伯先天性黑蒙病中起关键作用。它们进一步突出了基于该蛋白特定亚型的调控表达和激活的Bax依赖性凋亡的新调控机制。
