title: Triggering of Bcl-2-related pathway is associated with apoptosis of photoreceptors in Rpe65-/- mouse model of Leber's congenital amaurosis.
abstract: 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.
authors.affiliation: Institute for Research in Ophthalmology (IRO), Avenue Grand-Champsec 64, 1950, Sion 4, Switzerland. sandra.cottet@irovision.ch
authors.forename: Sandra
authors.initials: S
authors.lastname: Cottet
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001766:Blindness / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010786:Photoreceptor Cells / Q000166:cytology*; D011487:Protein Conformation; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012160:Retina / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000502:physiology*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase