Triggering of Bcl-2-related pathway is associated with apoptosis of photoreceptors in Rpe65 ^{??/sup> mouse model of Leber¡¯s Congenital Amaurosis}

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• 作者：Sandra Cottet and Daniel F. Schorderet
• 关键词：Retinitis pigmentosa ; Leber’ ; s Congenital Amaurosis ; RPE65 ; Apoptosis ; Bax
• 刊名：Apoptosis
• 出版年：2008
• 出版时间：March, 2008
• 年：2008
• 卷：13
• 期：3
• 页码：329-342
• 全文大小：653.8 KB

文摘

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 α and β 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 β 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.