Article: article from journal or magazin.
Triggering of Bcl-2-related pathway is associated with apoptosis of photoreceptors in Rpe65-/- mouse model of Leber's congenital amaurosis.
Apoptosis : an international journal on programmed cell death
Publication types: Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
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.
Animals, Apoptosis/physiology, Blindness/congenital, Blindness/genetics, Carrier Proteins/genetics, Cell Line, Disease Models, Animal, Eye Proteins/genetics, Gene Expression Regulation, Humans, In Situ Nick-End Labeling, Mice, Mitochondria/metabolism, Photoreceptor Cells/cytology, Protein Conformation, Protein Transport, Proto-Oncogene Proteins c-bcl-2/physiology, Retina/metabolism, Up-Regulation, bcl-2-Associated X Protein/biosynthesis, bcl-2-Associated X Protein/physiology
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