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Published on: June 21, 2024
Targeted Activation of OGG1 Inhibits Paraptosis in Lens Epithelial Cells of Early Age-Related Cortical Cataract
Wenjing Geng1, Pengfei Li1, Guowei Zhang1
1Eye Institute, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China.
Purpose:
To investigate potential modes of programmed cell death in the lens epithelial cells (LECs) of patients with early age-related cortical cataract (ARCC) and to explore early-stage intervention strategies.
Methods:
Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using transmission electron microscopy. Cell death-associated protein markers were quantified via Western blot analysis, including those for paraptosis (ALIX, GRP78), apoptosis (cleaved caspase 3 and caspase 9), pyroptosis (N-GSDMD), and ferroptosis (GPX4). Intracellular vesicle-organelle colocalization was assessed through immunofluorescence. OGG1 protein expression and activity were evaluated through multiple methods, including Western blot, laser micro-irradiation, and immunofluorescence. The therapeutic potential of the OGG1 activator TH10785 on paraptosis was investigated using an ex vivo rat lens model.
Results:
Morphologic changes revealed significant endoplasmic reticulum (ER) swelling in ARCC patient LECs, with no characteristic apoptotic features. Paraptosis-related proteins exhibited significant alterations, while other cell death pathway markers (apoptosis, pyroptosis, and ferroptosis) remained unchanged. In the reactive oxygen species-induced paraptosis model, vesicular structures showed exclusive colocalization with ER-specific fluorescence. Elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine were observed concurrent with decreased OGG1 activity. The OGG1 activator TH10785 showed efficacy in suppressing LECs paraptosis in ex vivo rat lens cultures.
Conclusions:
Paraptosis was identified in the LECs of patients with early ARCC. TH10785 activates OGG1 to suppress paraptosis in LECs, suggesting a novel therapeutic approach for early ARCC intervention.
Insights
Paraptosis, a form of cell death, is identified in early age-related cortical cataract (ARCC) lens cells. An OGG1 activator, TH10785, shows promise in suppressing this cell death for early ARCC intervention.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Age-related cortical cataract (ARCC) is a leading cause of vision impairment.
- The precise mechanisms of cell death in early ARCC lens epithelial cells (LECs) remain incompletely understood.
- Identifying specific cell death pathways is crucial for developing targeted interventions.
Purpose of the Study:
- To investigate programmed cell death modes in LECs from early ARCC patients.
- To explore potential early-stage therapeutic strategies for ARCC.
Main Methods:
- Analysis of LECs from early ARCC patients using transmission electron microscopy and Western blotting.
- Quantification of cell death markers for paraptosis, apoptosis, pyroptosis, and ferroptosis.
- Evaluation of OGG1 expression, activity, and the therapeutic effect of OGG1 activator TH10785 in an ex vivo rat lens model.
Main Results:
- Significant endoplasmic reticulum swelling and paraptosis marker alterations were observed in ARCC LECs, without apoptotic features.
- Vesicular structures colocalized with ER markers in a reactive oxygen species-induced paraptosis model.
- Elevated DNA damage markers and decreased OGG1 activity were noted; TH10785 suppressed paraptosis in rat lenses.
Conclusions:
- Paraptosis is a key cell death mechanism in LECs of early ARCC patients.
- TH10785, by activating OGG1, effectively suppresses LEC paraptosis.
- This suggests a novel therapeutic avenue for early ARCC intervention.
