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Beatrice M Tam, Orson L Moritz, Serena Chan; Repeated synchronous photoactivation of mutant rhodopsin molecules induces rapid retinal degeneration in a T4K rhodopsin model of RP.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5406.
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© ARVO (1962-2015); The Authors (2016-present)
The rhodopsin mutation T4K is associated with sector RP in humans and causes light dependent retinal degeneration in transgenic X. laevis. Previously we demonstrated that this retinal degeneration is associated with photoactivation of the mutant protein. Our objective is to elucidate the pathogenic mechanisms underlying the light dependence of this RP model.
Transgenic lines of X. laevis were mated to produce tadpoles expressing human T4K rhodopsin in their rod photoreceptors. Transgenic tadpoles and their nontransgenic siblings were raised for 14 days in constant dark (which protects the retina from degeneration) and then exposed to varying light regimens in which we altered the light cycle frequency and/or light intensity. Following light exposure, animals were killed and one eye was processed for histology and the other for protein analysis.
We compared retinal degeneration in T4K rhodopsin transgenic X. laevis under conditions of bright constant light, constant dark, and bright cyclic light, as well as constant intermediate and dim light intensities. We found that the retinal degeneration was significantly more severe in cyclic light than any other condition, and both constant dark and constant light were protective relative to cyclic light. We further varied the cyclic light interval, and found that degeneration was maximal in one hour on/one hour off conditions. Interestingly, more frequent intervals were less damaging suggesting that multiple rounds of rhodopsin regeneration and activation are required for cellular toxicity. In animals exposed to 1:1 cyclic light. Retinal degeneration was largely complete within 48 hours. Constant dim light was more protective than constant bright light.
We have identified an unusual retinal degeneration that is protected by both dark rearing and rearing in constant light. Our results suggest that retinal degeneration requires repeated simultaneous activation of a substantial proportion of the mutant rhodopsin present in photoreceptor outer segments.
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