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Kyoung-in Cho, MdEmdadul Haque, Minzhong Yu, Indulekha C. Lalitha, Nomingerel Tserentsoodol, Neal S. Peachey, Paulo A. Ferreira; Characterization of Cell Death Mechanisms in Cone and Rod Photoreceptors Caused by the Conditional Loss of Ran-binding Protein-2 (RanBP2) in M-cone Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2577.
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Photoreceptor cell death underlies severe visual impairments shared by numerous retinal diseases such as Retinitis Pigmentosa (RP) and age-related macular degeneration (AMD). Hence, the identification of molecular pathways triggering the death of photoreceptor neurons is crucial for the understanding of disease pathogenesis and development of novel therapies. The pleiotropic protein, RANBP2, is implicated in molecular processes, such as nucleocytoplasmic trafficking, oxidative stress signaling, proteostasis and lipid homeostasis, and mitochondria dynamics. Previously, we found that conditional ablation of RanBP2 in M-cone photoreceptors promotes the rampant death of these neurons within 2-weeks of cre-mediated RanBP2 excision. This study aims at testing the hypothesis that conditional loss of RanBP2 expression in M-cones promotes novel molecular mechanisms underlying cone degeneration.
The retinas of mice with a loxP-flanked RANBP2 gene and expressing Cre under control of the human L/M opsin promoter were analyzed by immunohistochemistry, electron microscopy, electroretinogram recordings (ERG) of rod and cone responses, and biochemical assays.
Analyses of flat mounts and cross-sections of retinas indicate that loss of RANBP2 selectively in M-cones causes the rapid degeneration of M-cones by the activation of caspases 3/7, but not of other six caspases, yet without producing TUNEL-positive cells. Light microscopy and ultrastructural analyses of M-cones showed that the degeneration was accompanied first by the disintegration of outer segments followed by apparent vacuolization of cell bodies and inner fibers. Remarkably, these effects were accompanied by the formation of interstitial spaces between the dysmorphic cones and immediate neighboring rods with limited disintegration of the plasma membrane and morphological changes, and apparent TUNEL-positive rods. We identified a novel retinal metalloproteinase, which is strongly up-regulated in the retina of mice with RANBP2 ablation selectively in M-cones. ERGs of dark-adapted b- and a-waves of rods indicate a small decrease of the amplitude of these waves throughout the progression of M-cone degeneration, whereas deficits of the amplitude of cone ERGs were clear by P15 and thereafter decreased rapidly with almost no electrophysiological responses retained by P22.
The data support that the loss of RANBP2 in M-cones triggers a non-canonical programmed cell death pathway in M-cones, whereas neighboring rods undergo non-autonomous cell death or impairment as manifested by a decrease in ERG amplitudes and morphological changes.
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