Journal of the Formosan Medical Association = Taiwan yi zhi · 2026
DAPL1 deficiency impairs autophagy in retinal pigment epithelium to drive age-dependent retinal pathologies.
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Chen Huaicheng, Tan Qiufan, Hu Yishan, Liu Liping, Liang Xiaoxin, Hou Ling
Аннотация
BACKGROUND/PURPOSE: Age-related retinopathy, mainly age-related macular degeneration (AMD), is a major cause of irreversible blindness in the elderly worldwide. Its precise mechanisms remain incompletely understood. Although autophagy deficiency in retinal pigment epithelial (RPE) cells is associated with AMD in patients, the regulatory pathways involved are still unclear. The research purpose is to investigate the functional role and underlying mechanism of DAPL1 in autophagy deficiency in the age-dependent retinal pathologies.
METHODS: In this study, 18-month-old wild-type (WT) and Dapl1-/- mice were used. Fundus photography and optical coherence tomography (OCT) were employed to detect morphological abnormalities. Immunofluorescence was performed to examine GFAP, Rhodopsin/Opsin, IBA1, and LC3, and on RPE flat mounts for ZO-1. Lipid deposition was analyzed by Oil Red O staining. To investigate downstream mediators of DAPL1, western and RT-qPCR were used to identify and validate candidate genes, followed by functional validation using lentiviral overexpression and RNA interference.
RESULTS: At 18 months of age, Dapl1-deficient mice exhibit age-related retinal dysfunction and structural abnormalities. These include increased retinal stress, damage to photoreceptors and RPE cells, lipid accumulation, and microglial activation. Autophagy is impaired in the RPE cells of Dapl1-deficient mice. DAPL1 overexpression in RPE cells enhances autophagy activity. Furthermore, DAPL1 suppresses the expression of E2F1 and c-MYC. This downregulates mTOR and upregulates the expression of ATG16 and Beclin1 through DAPK1 in RPE cells, promoting autophagy.
CONCLUSION: These findings suggest DAPL1 is a novel regulator of autophagy in RPE cells, and its deficiency increases susceptibility to age-dependent retinal pathologies in mice.
METHODS: In this study, 18-month-old wild-type (WT) and Dapl1-/- mice were used. Fundus photography and optical coherence tomography (OCT) were employed to detect morphological abnormalities. Immunofluorescence was performed to examine GFAP, Rhodopsin/Opsin, IBA1, and LC3, and on RPE flat mounts for ZO-1. Lipid deposition was analyzed by Oil Red O staining. To investigate downstream mediators of DAPL1, western and RT-qPCR were used to identify and validate candidate genes, followed by functional validation using lentiviral overexpression and RNA interference.
RESULTS: At 18 months of age, Dapl1-deficient mice exhibit age-related retinal dysfunction and structural abnormalities. These include increased retinal stress, damage to photoreceptors and RPE cells, lipid accumulation, and microglial activation. Autophagy is impaired in the RPE cells of Dapl1-deficient mice. DAPL1 overexpression in RPE cells enhances autophagy activity. Furthermore, DAPL1 suppresses the expression of E2F1 and c-MYC. This downregulates mTOR and upregulates the expression of ATG16 and Beclin1 through DAPK1 in RPE cells, promoting autophagy.
CONCLUSION: These findings suggest DAPL1 is a novel regulator of autophagy in RPE cells, and its deficiency increases susceptibility to age-dependent retinal pathologies in mice.