Protein-thiol mixed disulfides in human lens

Area of Science:

• Biochemistry
• Ophthalmology
• Gerontology

Background:

• Protein-thiol mixed disulfide formation is linked to protein aggregation in cataractogenesis.
• Two key thiols bound to proteins are glutathione (GSH) and cysteine, forming protein-S-glutathione (PSSG) and protein-S-cysteine (PSSC).

Purpose of the Study:

• To investigate the presence and distribution of PSSG and PSSC in animal lenses.
• To analyze the impact of aging on PSSG and PSSC levels in human donor lenses.
• To explore the influence of oxidative stress on protein-thiol mixed disulfides in the human lens.

Main Methods:

• Quantification of PSSG and PSSC levels across various animal species.
• Analysis of PSSG and PSSC levels in human donor lenses across a wide age range (3 months to 88 years).
• Localization studies of PSSG and PSSC within the human lens (nuclear vs. cortical regions, soluble vs. insoluble fractions).

Main Results:

• PSSG and PSSC are ubiquitous in animal lenses, with highest concentrations in human, dog, and rat lenses.
• The ratio of PSSG to PSSC varies significantly among species (e.g., 1/10 in rat, 4/1 in human/dog, 2/1 in monkey).
• Lens PSSC levels increase linearly with age in humans, while PSSG exhibits a complex triphasic pattern. Oxidative stress exacerbates protein modification.

Conclusions:

• Species-specific variations in PSSG/PSSC ratios and age-dependent changes in human lenses suggest a role in lens aging and cataractogenesis.
• PSSC accumulation in the nuclear region and insoluble proteins indicates a potential link to age-related lens opacities.
• Oxidative stress further contributes to protein modification via mixed disulfide formation in the aging human lens.