The decreased antioxidant capacity in the retinal pigment epithelium (RPE) is the hallmark of retinal degenerative diseases including age-related macular degeneration (AMD). Nevertheless, the exact regulatory mechanisms underlying the pathogenesis of retinal degenerations remain largely unknown. Here we show in mice that deficiencies in Dapl1, a susceptibility gene for human AMD, impair the antioxidant capacity of the RPE and lead to age-related retinal degeneration in the 18-month-old mice homozygous for a partial deletion of Dapl1. Dapl1-deficiency is associated with a reduction of the RPE's antioxidant capacity, and experimental re-expression of Dapl1 reverses this reduction and protects the retina from oxidative damage. Mechanistically, DAPL1 directly binds the transcription factor E2F4 and inhibits the expression of MYC, leading to upregulation of the transcription factor MITF and its targets NRF2 and PGC1α, both of which regulate the RPE's antioxidant function. When MITF is experimentally overexpressed in the RPE of DAPL1 deficient mice, antioxidation is restored and retinas are protected from degeneration. These findings suggest that the DAPL1-MITF axis functions as a novel regulator of the antioxidant defense system of the RPE and may play a critical role in the pathogenesis of age-related retinal degenerative diseases.

视网膜色素上皮 (RPE) 的抗氧化能力下降是包括年龄相关性黄斑变性 (AMD) 在内的视网膜退行性疾病的标志。然而，视网膜变性发病机制的确切调节机制在很大程度上仍然未知。在这里，我们在小鼠身上发现人类 AMD 易感基因Dapl1的缺陷会损害 RPE 的抗氧化能力，并导致 18 个月大的 Dapl1 纯合子小鼠出现年龄相关性视网膜变性。Dapl1缺陷与 RPE 抗氧化能力的降低以及Dapl1的实验再表达有关逆转这种减少并保护视网膜免受氧化损伤。从机制上讲，DAPL1 直接结合转录因子 E2F4 并抑制 MYC 的表达，导致转录因子 MITF 及其靶标 NRF2 和 PGC1α 的上调，这两者都调节 RPE 的抗氧化功能。当 MITF 在 DAPL1 缺陷小鼠的 RPE 中实验性过度表达时，抗氧化作用得到恢复，视网膜免受退化。这些发现表明 DAPL1-MITF 轴作为 RPE 抗氧化防御系统的新型调节剂发挥作用，并可能在与年龄相关的视网膜退行性疾病的发病机制中发挥关键作用。