DAPL1 deficiency in mice impairs antioxidant defenses in the RPE and leads to retinal degeneration with AMD-like features

The decreased antioxidant capacity in the retinal pigment epithelium (RPE) is the hallmark of retinal degener-ative diseases including age-related macular degeneration (AMD). Nevertheless, the exact regulatory mecha-nisms 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 tran-scription factor MITF and its targets NRF2 and PGC1 alpha, 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.

Automated summary

Deficiencies in Dapl1 lead to decreased antioxidant capacity in the RPE, resulting in age-related retinal degeneration. Dapl1 regulates the antioxidant function of the RPE by inhibiting MYC expression, protecting the retina from oxidative damage, and potentially playing a critical role in the pathogenesis of age-related retinal degenerative diseases.