J Neurosci 2024 Aug 01; doi: 10.1523/JNEUROSCI.0453-24.2024.

Synchronized photoactivation of T4K rhodopsin causes a chromophore-dependent retinal degeneration that is moderated by interaction with phototransduction cascade components.

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Multiple mutations in the Rhodopsin gene cause sector retinitis pigmentosa in humans and a corresponding light-exacerbated retinal degeneration (RD) in animal models. Previously we have shown that T4K rhodopsin requires photoactivation to exert its toxic effect. Here we further investigated the mechanisms involved in rod cell death caused by T4K rhodopsin in mixed male and female Xenopus laevis In this model, RD was prevented by rearing animals in constant darkness but surprisingly also in constant light. RD was maximized by light cycles containing at least one hour of darkness and 20 minutes of light exposure, light intensities > 750 lux, and by sudden light onset. Under conditions of frequent light cycling, RD occured rapidly and synchronously, with massive shedding of ROS fragments into the RPE initiated within hours, and subsequent death and phagocytosis of rod cell bodies. RD was minimized by reduced light levels, pre-treatment with constant light, and gradual light onset. RD was prevented by genetic ablation of the retinal isomerohydrolase RPE65, and exacerbated by ablation of phototransduction components GNAT1, SAG, and GRK1. Our results indicate that photoactivated T4K rhodopsin is toxic, that cell death requires synchronized photoactivation of T4K rhodopsin, and that toxicity is mitigated by interaction with other rod outer segment proteins regardless of whether they participate in activation or shutoff of phototransduction. In contrast, RD caused by P23H rhodopsin does not require photoactivation of the mutant protein, as it was exacerbated by RPE65 ablation, suggesting that these phenotypically similar disorders may require different treatment strategies.Significance Statement Many different rhodopsin mutations are linked to the inherited degenerative disease retinitis pigmentosa. Although the end result in each case is the loss of photoreceptor cells and blindness, not all mutations cause cell death via the same mechanism. In order to design and test treatment therapies that target the disease at points as upstream as possible in the process, we require detailed understanding of the range and nature of these disease mechanisms. This study using a transgenic Xenopus laevis model has extended our understanding of how T4K rhodopsin and related mutations cause rod cell photoreceptor death via a phototoxic product, and how this mechanism differs from the more extensively researched protein misfolding mechanism underlying cell death caused by P23H rhodopsin.

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Species referenced: Xenopus laevis
Genes referenced: gnat1 grk1 rho rpe rpe65 sag

???displayArticle.disOnts??? retinitis pigmentosa
???displayArticle.omims??? RETINITIS PIGMENTOSA; RP