Comparative proteomics of human anterior lens capsules reveals ATP6V1A-associated lysosomal dysregulation in age-related cataract with primary angle-closure glaucoma

Abstract

Lens-related mechanisms in primary angle-closure glaucoma (PACG) remain incompletely defined. The anterior lens capsule (ALC) is a biologically active interface, but its molecular landscape in PACG is largely unknown. We aimed to define proteomic alterations in human ALCs from age-related cataract (ARC) with PACG and to evaluate whether lysosome-associated changes are implicated. We performed comparative data-independent acquisition proteomic profiling of human ALC specimens from patients with ARC alone and ARC combined with PACG. After quality control, 13 ARC and 10 PACG samples were included. Differential proteins were analyzed by enrichment, network, and receiver operating characteristic analyses. ATP6V1A was further evaluated in human ALC flat mounts, cell and animal stress models, peripheral blood mononuclear cells (PBMCs) from an additional small clinical cohort, and an exploratory UK Biobank (UKB) plasma proteomic dataset. A total of 1262 differentially expressed proteins were identified in PACG-associated ALCs. Proteins reduced in PACG were enriched for proteostasis-related chaperone and neddylation networks and converged on lysosome-related dysfunction. ATP6V1A and additional V-ATPase subunits, LAMP2, and Rag GTPase family members were coordinately decreased. Proteins increased in PACG were enriched for extracellular matrix remodeling and lipid/glycan metabolic pathways. Reduced ATP6V1A was confirmed in human ALC flat mounts, pressure-stressed lens epithelial cells, retinal stress models, and PBMCs from patients with PACG. Pharmacologic V-ATPase inhibition disrupted lysosomal homeostasis before overt loss of cell viability. UKB plasma proteomics did not recapitulate the ATP6V1A signal, but provided external support for glaucoma-associated lens-related and metabolic alterations. PACG-associated ALCs show a distinct molecular signature characterized by impaired proteostasis and ATP6V1A-associated lysosomal dysregulation. These findings identify ATP6V1A-associated lysosomal dysfunction as a candidate molecular link between elevated IOP, lens epithelial injury, and the coexistence of PACG and ARC.