Bisretinoids mediate light sensitivity resulting in photoreceptor cell degeneration in mice lacking the receptor tyrosine kinase Mer.

The receptor tyrosine kinase Mer is expressed by retinal pigment epithelial (RPE) cells and participates in photoreceptor outer-segment phagocytosis, a process enabling membrane renewal. Mutations in the gene encoding MERTK cause blinding retinitis pigmentosa in humans. Targeted disruption in mice causes defective RPE-mediated phagocytosis of the outer segments, leading to deposition of autofluorescent debris at the RPE-photoreceptor cell interface, followed by photoreceptor cell degeneration. Here, we show that retinaldehyde adducts (bisretinoid fluorophores) that form in photoreceptor outer segments occupy the unphagocytosed outer-segment debris that accumulates in mice. Bisretinoids measured by HPLC were elevated in mice compared with WT animals. Bisretinoids were also more abundant in albino mice expressing leucine at position 450 of the isomerase RPE65 (Rpe65-Leu450) rather than the variant methionine (Rpe65-450Met) that yields lower bisretinoid levels. In Royal College of Surgeons rats having dysfunctional , bisretinoids were higher than in WT rats. Intensities of fundus autofluorescence were higher in mice than in WT mice and peaked earlier in albino /Rpe65-Leu450 mice than in albino /Rpe65-450Met mice. Of note, the rate of photoreceptor cell degeneration was more rapid in albino mice exposed to higher levels of intraocular light (albino pigmented mice) and in mice carrying Rpe65-Leu450 than in Rpe65-450Met mice, revealing a link between bisretinoid accumulation and light-mediated acceleration of photoreceptor cell degeneration. In conclusion, the light sensitivity of photoreceptor cell degeneration arising from deficiency is consistent with the known phototoxicity of bisretinoids.