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H. Moaven, Y. Koike, B. Soreghan, V. V. Gurevich, J. Chen; Expression of Arrestin1 Splice Variant, p44, Rescues Retinal Degeneration in K296E Mouse Models of ADRP. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2990.
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We have previously demonstrated that K296E, a human rod opsin point mutation, leads to autosomal dominant retinitis pigmentosa through an accumulation of stable K296E/Arrestin1 complex that is toxic to mammalian photoreceptors. We hypothesize that endocytosis of this complex may be the catalyst for photoreceptor cell death.
p44 is a bovine rod arrestin1 splice variant that deactivates light-activated, phosphorylated rhodopsin but lacks the predicted AP-2 binding site for endocytosis. p44 was expressed in the rod photoreceptor cells of transgenic mice using the 4.4 kb mouse rod opsin promoter. Mice expressing p44 were crossed with K296E transgenic mice and rod arrestin1 knockout (Arr1-/-) mice to obtain mice that expressed K296E and p44 in the Arr1-/- background. We examined retinal morphology of these mice and their littermate controls by measuring the outer nuclear layer (ONL) thickness of sectioned retinas embedded in epoxy resin. The interaction and localization of p44 and K296E was observed using immunocytochemistry (ICC). Western blot analysis was used to confirm presence or absence of p44 and K296E.
Expression of p44 in K296E mice vastly curbed retinal degeneration in the Arr1-/- background when compared with mice that expressed K296E alone in the Arr1+/+, Arr1+/-, or Arr1-/- backgrounds. ONL thickness and outer segment length was comparable to wildtype mice. Indeed, p44 appears to bind K296E, seen as co-localization in ICC staining and western blots. However, there was some K296E mislocalization still observed throughout the photoreceptor.
Our results suggest that p44’s interaction with K296E can rescue the photoreceptor from retinal degeneration. This result supports the stated hypothesis that endocytosis of K296E/arrestin1 complex is a necessary step to generate the cell death signal.
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