Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4 -/- Rdh8 -/- mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4 -/- Rdh8 -/- mice. Of note, intraperitoneal administration of JNK-IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4 -/- Rdh8 -/- mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.

中文翻译：

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JNK信号的激活促进小鼠中全反式视网膜诱导的感光细胞凋亡。

全反式视网膜（atRAL）（视网膜中视觉（类维生素A）循环的一个组成部分）的清除中断可能会导致常染色体隐性Stargardt病（STGD1）和与干龄相关的黄斑变性（AMD）的感光细胞萎缩。但是，atRAL诱导的感光细胞丧失的潜在机制仍然难以捉摸。在这里，我们报告说atRAL激活c-Jun N端激酶（JNK）信号至少部分通过活性氧的产生，从而促进线粒体介导的胱天蛋白酶和DNA损伤依赖的感光细胞凋亡。JNK激活导致atRAL暴露的感光细胞线粒体受损，导致Bcl2凋亡调节剂（Bcl2）的表达降低，Bcl2拮抗剂/杀手（Bak）的水平增加以及细胞色素c（Cyt c）释放到细胞质中。胞质Cyt c特异激发caspase-9和caspase-3活化，从而启动细胞凋亡。在加载了atRAL的感光细胞中JNK的磷酸化诱导了γH2AX的出现，γH2AX是DNA损伤的敏感标记，并且还与凋亡的发生有关。JNK信号的抑制保护感光细胞免受atRAL诱导的凋亡。此外，缺少Jnk1和Jnk2基因的感光细胞对atRAL相关的细胞毒性具有更强的抵抗力。Abca4-/-Rdh8-/-小鼠模型显示了atRAL清除缺陷，这是STGD1和干AMD的特征。我们发现，JNK信号传导在光照的Abca4-/-Rdh8-/-小鼠的神经视网膜中被激活。值得注意的是，抑制JNK信号传导的JNK-IN-8腹膜内给药，在光照下的Abca4-/-Rdh8-/-小鼠中有效地改善了感光细胞的变性和凋亡。我们提出，JNK信号传导的药理抑制作用可能代表一种预防因atRAL超负荷引起的视网膜病变中光感受器丢失的治疗策略。