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other·ophthalmology, retina, preclinical research, biomedical research·PMC10031543

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

Redox Biology · 13 authors, 4 centres

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Using mouse models, researchers found that the absence of DAPL1 impairs antioxidant defense in the retinal pigment epithelium (RPE) and causes age-related retinal degeneration with features similar to age-related macular degeneration (AMD).

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This preclinical study used Dapl1-deficient and Dapl1-overexpressing mouse models to investigate the role of DAPL1 in retinal health. The researchers demonstrated that DAPL1 deficiency leads to impaired antioxidant capacity in RPE cells and age-dependent retinal degeneration. Mechanistic analysis revealed a pathway where DAPL1 binds to E2F4 to inhibit MYC expression, which in turn promotes MITF expression, subsequently activating antioxidant genes NRF2 and PGC1α. Overexpression of DAPL1 or MITF in the RPE of Dapl1-deficient mice rescued antioxidant function and protected against degeneration. The findings provide mechanistic insights into how a genetic susceptibility factor for AMD might contribute to retinal degeneration through oxidative stress pathways.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10031543

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

Redox Biology

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ABSTRACT

Abstract 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. Keywords: Oxidative stress, MITF, Pigment cell, AMD, AAV

CITATION EXPORT

Xiaoyin Ma, Huaicheng Chen, Shuhui Jian et al.. DAPL1 deficiency in mice impairs antioxidant defenses in the RPE and leads to retinal degeneration with AMD-like features. Redox Biology. (2023). https://doi.org/10.1016/j.redox.2023.102675

AUTHORS

13 · 4 CENTRES

Xiaoyin Ma, Huaicheng Chen, Shuhui Jian, Junhao He, Youjia Liu, Shuxian Han, Lifu Chang, Pingping Li, Ying-ao Chen, Xiaoyan Liu, Xiaojuan Hu, Yu Chen, Ling Hou

aLaboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China
bState Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, 325003, China
cDepartment of Ophthalmology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
dThe Affiliated Eye Hospital of Nanjing Medical University, Nanjing, 210029, China