a-cost-effective-minimally-invasive-protocol-for-chronic-multi-site

A Cost-Effective and Minimally Invasive Protocol for Chronic Multi-Site Electroencephalography Recording in Freely Moving Mice

Electroencephalography (EEG) serves as a fundamental tool for tracking electrical activity in the brain and has become increasingly important in both ...

Medical College of Georgia at Augusta University

National Institute of Biotechnology

A sharp drop in lenticular glutathione (GSH) plays a pivotal role in age-related cataract (ARC) formation. Despite recognizing GSH's importance in lens defense for decades, its decline with age remains puzzling. Our recent study revealed an age-related truncation affecting the essential GSH biosynthesis enzyme, the γ-glutamylcysteine ligase catalytic subunit (GCLC), at aspartate residue 499. Intriguingly, these truncated GCLC fragments compete with full-length GCLC in forming a heterocomplex with the modifier subunit (GCLM) but exhibit markedly reduced enzymatic activity. Crucially, using an aspartate-to-glutamate mutation knock-in (D499E-KI) mouse model that blocks GCLC truncation, we observed a notable delay in ARC formation compared to WT mice: Nearly 50% of D499E-KI mice remained cataract-free versus ~20% of the WT mice at their age of 20 months. Our findings concerning age-related GCLC truncation might be the key to understanding the profound reduction in lens GSH with age. By halting GCLC truncation, we can rejuvenate lens GSH levels and considerably postpone cataract onset.

Prevention of age-related truncation of γ-glutamylcysteine ligase catalytic subunit (GCLC) delays cataract formation.

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract.

There is currently limited information regarding inflammation and cytokine levels in the aqueous humor (AH) of adult patients with cataract who have undergone phacoemulsification cataract extraction without other ocular comorbidities.

Elevated Inflammatory Cytokines Persist in the Aqueous Humor Years After Cataract Surgery.

Cataract surgery is the most commonly performed ophthalmic procedure worldwide, yet long-term molecular adaptations of lens epithelial cells (LECs) following surgery remain poorly understood.

Transcriptomic Analysis of Human Lens Epithelium Tissue With and Without Cataract Surgery: Uncovering Novel Pathways of Post-Surgical Lens Epithelium Remodeling.

Article	Year
Prevention of age-related truncation of γ-glutamylcysteine ligase catalytic subunit (GCLC) delays cataract formation. Science advances\| PubMed ID: 38669339	2024
Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 39560644	2024
Elevated Inflammatory Cytokines Persist in the Aqueous Humor Years After Cataract Surgery. Investigative ophthalmology & visual science\| PubMed ID: 40183733	2025
Transcriptomic Analysis of Human Lens Epithelium Tissue With and Without Cataract Surgery: Uncovering Novel Pathways of Post-Surgical Lens Epithelium Remodeling. Investigative ophthalmology & visual science\| PubMed ID: 40643341	2025

Kazi Rafsan Radeen

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