bims-mideyd 2025-06-08 papers

Biomed J. 2025 Jun 02. pii: S2319-4170(25)00049-6. [Epub ahead of print] 100875

IRE1-Mediated Endoplasmic Reticulum Stress Response Regulates Oxidative Damage in CYP4V2 Deficient Human Retinal Pigment Epithelial Cells.

Yu-Ting Hsiao, Chang-Chun Hsiao, Jong-Jer Lee.

BACKGROUND: Given the role of polyunsaturated fatty acid (PUFA) overload and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells in causing retinal degeneration in Bietti crystalline dystrophy (BCD), we aimed to identify the pathways responsible for intracellular oxidative stress and mitochondrial damage in CYP4V2-deficient RPE cells.
MATERIALS AND METHODS: Proteomic analysis of control and CYP4V2-knockdown (KD) ARPE-19 cells revealed that endoplasmic reticulum (ER) stress was the most enriched pathway. The effects of CYP4V2 deficiency on intracellular reactive oxygen species, mitochondrial integrity, and ATP production were assessed.
RESULTS: Inositol-requiring enzyme 1 α (IRE1α) inhibitors suppressed upregulation of endoplasmic reticulum oxidoreductase 1 alpha (ERO1-Lα) protein expression, which contributed to ER-associated oxidative stress. Loss of mitochondrial transmembrane potential and reduced ATP production were mitigated with IRE1α inhibitor in CYP4V2-KD ARPE-19 cells.
CONCLUSIONS: Our findings reveal a novel regulatory mechanism involving potential reduction in PUFA utilization, IRE1α signaling mediated ER oxidative stress, and mitochondrial dysfunction in BCD, potentially offering future therapeutic avenues.

Keywords: Bietti Crystalline Dystrophy; CYP4V2; endoplasmic reticulum stress; inherited retinal diseases; reactive oxygen species

DOI: https://doi.org/10.1016/j.bj.2025.100875

Exp Eye Res. 2025 Jun 02. pii: S0014-4835(25)00244-1. [Epub ahead of print]258 110473

DAPL1 inhibits epithelial-mesenchymal transition of retinal pigment epithelial cells by regulating the TGF-β/MITF pathway.

Yaqi You, Youjia Liu, Lijing Huang, Wan-Ni Lu, Yingxin Zhang, Tianyin Nie, Meiyu Jing, J Fielding Hejtmancik, Xingyi Li, Ling Hou, Xiaoyin Ma.

Epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a critical factor in the development of retinopathies, including proliferative vitreoretinopathy (PVR) and age-related macular degeneration (AMD), which are the leading causes of blindness worldwide. Deficiency in DAPL1 can induce RPE-EMT in vivo, and Dapl1 knockout mice (Dapl1 -/-) are prone to PVR, while aged Dapl1 -/- mice display AMD-like pathological features. However, the molecular mechanisms through which DAPL1 regulates RPE-EMT remain largely unknown. Here, using Dapl1 -/- mice and DAPL1 knockdown or overexpression RPE cells, we show that DAPL1 inhibits RPE-EMT by regulating the TGF-β/MITF signaling pathway, a critical signaling pathway/transcription factor in RPE cells. Overexpression of DAPL1 inhibits TGF-β-induced RPE-EMT, while deletion of Dapl1 in mice activates TGF-β signaling, decreases MITF expression, and promotes RPE-EMT under physiological or PVR pathological conditions. Gene therapy demonstrates that transgenic overexpression of MITF in Dapl1 -/- mice inhibits RPE-EMT in vivo and prevents retinal detachment-induced PVR pathological progress, offering hope for future treatment. Similarly, pharmacological therapy with Isoviolanthin, a flavonoid glycoside isolated from traditional medicinal herbs, inhibits TGF-β signaling and increases MITF expression in RPE cells in Dapl1 -/- mice, which then effectively rescues experimental PVR in Dapl1 -/- mice. These results suggest that DAPL1 regulates RPE-EMT at least partial through the TGF-β/MITF pathway and that targeting the TGF-β/MITF pathway could be a potential therapeutic strategy to treat Dapl1 deficiency-induced RPE-EMT-related retinal diseases, instilling hope for the future of retinal disease treatment.

Keywords: DAPL1; EMT; MITF; PVR; RPE; TGF-β signaling

DOI: https://doi.org/10.1016/j.exer.2025.110473

Ageing Res Rev. 2025 Jun 03. pii: S1568-1637(25)00142-4. [Epub ahead of print]110 102796

The role of secretory autophagy and exosomes in the accumulation of drusen during the development of age-related macular degeneration (AMD).

Juha M T Hyttinen, Minna Niittykoski, Kai Kaarniranta.

Age-related macular degeneration (AMD) is the most common disease of the elderly that leads to the loss of sight. So far, no satisfactory therapy exists for this complex eye disease. The appearance of extracellular deposits, called drusen, on the outside of the retinal pigment epithelium (RPE) is considered to be the main clinical hallmark of AMD. Whilst the mechanisms of drusen formation are not well known, secreted material from the RPE, during its degeneration, is thought to contribute to the development of AMD. Various unconventional protein secretion (UPS) pathways are considered to be routes for the delivery of material which form the drusen. The two main forms of UPS are secretory autophagy, which is responsible for the cleansing of cellular debris from the RPE cells and endosomal secretion which carries material outside of the cell via exosomes. These pathways are unconventional in the sense that they comprise the delivery of material to the exterior of cells by bypassing the Golgi apparatus. Although secretory autophagy and exosome release are regarded as different routes by which cells exude material, they share similarities, such as common molecular participants and that their routes converge. Therefore, manipulation of these two processes might be useful in a therapy against AMD by diminishing the destructive drusen progression in the vicinity of the RPE.

Keywords: Drusen; exosome; extracellular vesicle; retinal pigment epithelium; secretory autophagy; unconventional protein secretion

DOI: https://doi.org/10.1016/j.arr.2025.102796

Invest Ophthalmol Vis Sci. 2025 Jun 02. 66(6): 8

PRMT5 Regulates Senescence in Retinal Ganglion Cells by Targeting the Wnt/β-Catenin Signaling Cascade.

Yumeng Zhang, Hanwen Huang, Huimin Zhong, Yang Zhang, Siqi He, Yanzhi Guo, Yiwei Wang, Ping Huang, Shouyue Huang, Yisheng Zhong.

Purpose: In patients with glaucoma, progressive degeneration of retinal ganglion cells (RGCs) leads to irreversible visual impairments. Despite recent studies indicating that senescence is associated with RGC death, the underlying molecular mechanisms remain unclear.
Methods: The chronic ocular hypertension (COH) mouse model was established by infusing a crosslinking hydrogel into the anterior chamber. Cellular senescence was evaluated using Western blot analysis, cell cycle, senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay, and immunofluorescence. Functional experiments were conducted in retinal precursor (R28) cells through small interfering RNA-mediated knockdown and plasmid-mediated overexpression. Additionally, the role of the protein arginine methyltransferase 5 (PRMT5)-regulated Wnt/β-catenin pathway in RGC senescence was investigated via intravitreal injection of GSK3326595 and CHIR99021 in mice.
Results: We demonstrate that PRMT5 is markedly downregulated in RGC in a COH mouse model, correlating with increased RGC senescence induced by elevated intraocular pressure. Silencing PRMT5 significantly accelerated senescence, as evidenced by increased SA-β-gal activity, cell cycle arrest, and senescence marker upregulation. Cotreatment with GSK3β inhibitor CHIR99021 alleviated hypoxia-induced senescence and reactivated the Wnt/β-catenin pathway, while the antagonist FH535 negated the neuroprotective effects of PRMT5 overexpression. In vivo, the PRMT5 inhibitor GSK3326595 reduced RGC survival and heightened senescence markers, whereas CHIR99021 mitigated RGC loss and restored Wnt/β-catenin signaling.
Conclusions: Taken together, these findings highlight the critical role of the PRMT5-regulated Wnt/β-catenin pathway in RGC senescence and neurodegeneration. Targeting this pathway represents a promising therapeutic strategy for glaucoma.

DOI: https://doi.org/10.1167/iovs.66.6.8