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K. Cho, H. YI, K. Searle, P. A. Ferreira; Molecular Analysis of Neuroprotection of Photoreceptor Neurons by RanBP2 Haploinsufficiency Upon Light-Induced Damage. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3227.
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The molecular components and pathways triggering the degeneration of photoreceptors neurons upon aging and light damage are largely elusive. We have recently reported that haploinsufficiency of Ran-binding protein-2 (RanBP2) confers neuroprotection to photoreceptors upon aging and light-induced oxidative stress by halting cell death and several subcellular phenotypes associated with damaged photoreceptors. Yet, the molecular bases underlying the RanBP2-mediated neuroprotection of photoreceptors upon aging and light remain unknown. The goal of this study is to identify photoreceptors components whose function is dependent on RanBP2 and modulated by light.
We employed inbred wild-type and RanBP2+/- mice to screen for proteins and metabolites whose levels were markedly affected by haploinsufficiency of RanBP2, light or diet. Immunological approaches and metabolite analyses were performed to examine and contrast the levels of proteins and metabolites of retinas and retina pigment epithelium (RPE) of wild-type and RanBP2+/- mice under the described experimental conditions.
We found that light and the levels of RanBP2 had a profound but selective effect in the modulation of specific partners of RanBP2 in the retina, whereas most of those effects were not observed in the RPE. Strikingly, fatty acid intake reversed the levels of some RanBP2 partners and the amount of photoreceptor cell death in a light and genotype-dependent fashion. We also identified members of a class of nuclear shuttling factors whose levels are modulated by RanBP2. Finally, diet had opposite effects on the levels of lipid metabolites in the retina and RPE tissues between wild-type and RanBP2+/- mice.
The data support the convergence of RanBP2-mediated signaling and trafficking pathways that couple environmental cues with molecular processes affecting the survival and function of photoreceptor neurons.
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