From the Departments of Ophthalmology and.
From the Departments of Ophthalmology and
J Biol Chem. 2018 Dec 14;293(50):19400-19410. doi: 10.1074/jbc.RA118.005949. Epub 2018 Oct 23.
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.
Mer 是一种受体酪氨酸激酶，由视网膜色素上皮 (RPE) 细胞表达，参与光感受器外节的吞噬作用，这一过程使膜得以更新。编码 MERTK 的基因突变会导致人类失明性视网膜色素变性。在小鼠中靶向破坏该基因会导致 RPE 介导的光感受器外节吞噬作用缺陷，导致外节的自荧光碎片在 RPE-光感受器细胞界面处沉积，随后光感受器细胞退化。在这里，我们表明，在光感受器外节中形成的视黄醛加合物（双视黄醛荧光团）占据了在 小鼠中积累的未被吞噬的外节碎片。与 WT 动物相比，用 HPLC 测量的双视黄醛在 小鼠中升高。在表达异构酶 RPE65 亮氨酸 450 位（Rpe65-Leu450）而不是产生较低双视黄醛水平的变异甲硫氨酸（Rpe65-450Met）的白化 小鼠中，双视黄醛也更丰富。在功能失调的皇家外科医生大鼠中，双视黄醛高于 WT 大鼠。与 WT 小鼠相比， 小鼠的眼底自发荧光强度更高，在白化 /Rpe65-Leu450 小鼠中比在白化 /Rpe65-450Met 小鼠中更早达到峰值。值得注意的是，在暴露于更高水平眼内光的白化 小鼠（白化 色素沉着小鼠）和携带 Rpe65-Leu450 的小鼠中，光感受器细胞退化的速度比携带 Rpe65-450Met 的小鼠更快，这表明双视黄醛积累与光介导的光感受器细胞退化加速之间存在联系。总之，由 缺乏引起的光感受器细胞退化的光敏感性与双视黄醛的已知光毒性一致。
