Primary angle-closure glaucoma, or PACG, is particularly prevalent in East Asian populations and arises when the iris physically blocks the drainage angle of the eye, driving up intraocular pressure. Because the lens sits directly behind the iris and a thickened or enlarged lens can itself promote closure of the angle, ophthalmologists have suspected for decades that lens biology and PACG are intertwined. What has been missing is a molecular account of that relationship. The anterior lens capsule is not merely packaging; it is a biologically active interface through which nutrients, signaling molecules, and waste products pass, and it houses the lens epithelial cells that maintain lens transparency throughout life. Until now, its protein landscape in PACG had remained essentially uncharted.

To build that map, the team turned to data-independent acquisition mass spectrometry, a proteomic technique that systematically measures thousands of proteins in a sample with high reproducibility. They compared anterior lens capsule specimens from patients undergoing cataract surgery who had age-related cataract alone against those who had cataract combined with PACG. After rigorous quality control, the analysis included 13 capsules from the cataract-only group and 10 from the PACG group. The comparison yielded a striking result: 1,262 proteins were differentially expressed between the two conditions, a scale of molecular remodeling far beyond what anyone had anticipated in this thin sheet of tissue.

The direction of the changes proved as informative as their number. Proteins that were reduced in PACG-associated capsules were enriched for networks governing proteostasis — the cell’s system for maintaining properly folded, functional proteins — including molecular chaperones and the neddylation pathway, a modification cascade that regulates protein degradation machinery. When the researchers ran these depleted proteins through enrichment and protein-protein interaction network analyses, they converged on a common hub: lysosome-related dysfunction. Lysosomes are the cell’s acidic recycling compartments, and their proper function depends on the vacuolar-type H+-ATPase, or V-ATPase, the proton pump that acidifies them. In the PACG capsules, ATP6V1A — a major subunit of that pump — was coordinately decreased alongside additional V-ATPase subunits, the lysosomal membrane protein LAMP2, and members of the Rag GTPase family, which regulate lysosomal signaling and nutrient sensing.

On the other side of the ledger, proteins that were increased in the PACG capsules were enriched for extracellular matrix remodeling and lipid and glycan metabolic pathways. That pattern suggests the capsule in PACG eyes is not simply degenerating; it is actively restructuring, with potential consequences for the mechanical relationships between the lens, iris, and drainage angle that define angle-closure disease. The researchers also performed receiver operating characteristic analyses to evaluate how well the differential proteins distinguished the two patient groups, an early step toward assessing whether such markers could eventually support clinical classification.

A single proteomic comparison, however compelling, cannot establish mechanism. So the team pursued ATP6V1A through an unusually thorough series of validation experiments. They confirmed reduced ATP6V1A in human anterior lens capsule flat mounts — whole-mount preparations that preserve the spatial architecture of the tissue. They then applied pressure stress to lens epithelial cells in culture, mimicking the mechanical environment of elevated intraocular pressure, and again observed ATP6V1A reduction. Retinal stress models, including ischemia-reperfusion paradigms, reproduced the signal, and — critically — so did peripheral blood mononuclear cells drawn from an additional small clinical cohort of patients with PACG. The consistency of the ATP6V1A decrease across human tissue, cell culture, animal models, and circulating immune cells lent substantial weight to the finding.

To test whether the loss of this proton pump actually matters functionally, the researchers used pharmacologic inhibition of the V-ATPase. The result was telling: disrupting the pump disturbed lysosomal homeostasis before any overt loss of cell viability could be detected. In other words, lysosomal dysfunction is not merely a late consequence of dying cells; it is an early event that precedes cell death, positioning it as a plausible upstream driver of lens epithelial injury rather than a passive byproduct. This temporal ordering is what elevates ATP6V1A from a correlational marker to a candidate mechanistic link between elevated intraocular pressure, lens epithelial damage, and the coexistence of PACG with age-related cataract.

The study also looked outward, to an independent population-scale dataset. The team examined an exploratory plasma proteomic dataset from the UK Biobank, a large-scale biomedical resource containing health data from hundreds of thousands of participants. Notably, the ATP6V1A signal itself did not reappear in circulating plasma, a reminder that tissue-resident protein changes do not always translate to the bloodstream and that plasma proteomics has inherent limitations for detecting organ-specific molecular events. Yet the UK Biobank analysis did provide external support for glaucoma-associated lens-related and metabolic alterations, independently corroborating the broader biological themes — if not the specific protein — that emerged from the capsule analysis.

The implications reach in several directions at once. Clinically, the findings suggest that the lens capsule could serve as a readout of molecular stress in glaucoma, and that ATP6V1A-associated lysosomal dysfunction might eventually inform how ophthalmologists understand and stratify patients whose cataract and glaucoma travel together. Mechanistically, the work reframes the lens as an active participant in PACG pathogenesis: pressure stress appears to erode the very machinery that lens epithelial cells need to recycle damaged proteins and maintain transparency, and that erosion is detectable in the capsule before cells die. If lysosomal failure is indeed an early, targetable event, it opens a conceptual window for interventions aimed at preserving proteostasis in the stressed lens — though the authors are careful to frame ATP6V1A as a candidate link, not a proven therapeutic target.

There are, of course, limits to what any single study can establish. The clinical cohorts were small — 13 and 10 capsules in the primary comparison, plus a modest validation cohort — and the UK Biobank plasma analysis failed to recapitulate the central signal. The study was conducted in accordance with the Declaration of Helsinki, approved by the Ethics Committee of Xiangya Hospital, and registered with the Chinese Clinical Trial Registry, with animal work separately approved by the institution’s animal care committee, but replication in larger and more diverse populations will be essential before these molecular signatures enter clinical practice. Even so, the scale of the proteomic remodeling documented here — more than 1,200 differential proteins converging on a single lysosomal hub — makes a persuasive case that the anterior lens capsule has been telling a molecular story all along, and that researchers are only now learning to read it. For the millions of people, particularly across Asia, who face the double burden of cataract and angle-closure glaucoma, that story may ultimately point toward new ways of protecting both the clarity of the lens and the survival of the sight it helps deliver.

Subject of Research: Proteomic identification of ATP6V1A-associated lysosomal dysregulation in the anterior lens capsule in age-related cataract with primary angle-closure glaucoma

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

Article References: Liu, J., Wang, J., Zeng, Y., Zhao, Z., Zhu, P., Liu, Y., Dong, Q., Zhao, J., Xia, X., Rong, R., & Ding, L. (2026). Comparative proteomics of human anterior lens capsules reveals ATP6V1A-associated lysosomal dysregulation in age-related cataract with primary angle-closure glaucoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08934-0

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08934-0

Keywords: primary angle-closure glaucoma, age-related cataract, anterior lens capsule, proteomics, ATP6V1A, lysosomal dysfunction, V-ATPase, lens epithelial cells, intraocular pressure, proteostasis, UK Biobank, mass spectrometry

The strongest case for this idea comes from genetics. Over the past twenty years, researchers hunting for genes that cause or raise the risk of neurodegenerative disorders have repeatedly landed on the endolysosomal system, the network of vesicles and organelles that ferries cargo to lysosomes for destruction. In Parkinson disease, the evidence is particularly compelling. A substantial proportion of genes linked to the condition encode proteins that are essential for lysosomal health, and the two most common genetic causes of Parkinson disease, mutations in GBA1 and LRRK2, both converge on lysosomal biology. Remarkably, both of these pathways are now being targeted in clinical trials, marking one of the first times that fundamental cell biology has been translated so directly into therapeutic strategies for a neurodegenerative illness.

The GBA1 story illustrates how a single gene can illuminate an entire disease mechanism. GBA1 encodes glucocerebrosidase, a lysosomal enzyme that breaks down fatty substances called glucosylceramides. People who carry one mutated copy of the gene are at markedly elevated risk of developing Parkinson disease, and studies have shown that reduced glucocerebrosidase activity in the substantia nigra, the brain region that degenerates in Parkinson disease, is associated with increased levels of alpha-synuclein, the protein that clumps into the Lewy bodies that define the disorder. Work from the Krainc laboratory and others has revealed a bidirectional loop: deficient glucocerebrosidase impairs the degradation of alpha-synuclein, while accumulating alpha-synuclein in turn blocks the delivery of fresh glucocerebrosidase to lysosomes, creating a vicious cycle of worsening protein aggregation and deepening lysosomal failure.

LRRK2, the other major Parkinson gene, tells a complementary story. This large kinase enzyme phosphorylates a family of Rab GTPases that regulate membrane trafficking throughout the cell. When lysosomes are damaged, LRRK2 is recruited to their surface through pathways involving the CASM machinery and GABARAP proteins, where it helps coordinate membrane repair and the removal of damaged lysosomal material. Pathogenic LRRK2 mutations boost kinase activity, producing enlarged lysosomes with reduced degradative capacity and impairing the clearance of alpha-synuclein. Because LRRK2 is also active in immune cells, its dysfunction extends to microglia, the brain’s resident immune cells, linking lysosomal failure to the neuroinflammation that accompanies neurodegeneration. LRRK2 kinase inhibitors, including the molecule BIIB122, have already been tested in patients, and a broad initiative called the LRRK2 investigative therapeutics exchange is working to overcome the remaining obstacles to translating this biology into disease-modifying therapies.

Beyond these headline genes, the review catalogues an expanding roster of lysosomal proteins implicated in Parkinson disease. Mutations in VPS35, a core component of the retromer complex that sorts cargo through endosomes, cause familial Parkinson disease and disrupt the retrieval of the chaperone-mediated autophagy receptor LAMP2A, which neurons use to deliver alpha-synuclein to lysosomes for destruction. ATP13A2, a lysosomal transporter whose loss causes an early-onset form of parkinsonism, exports polyamines from the lysosome, and its deficiency triggers lysosomal dysfunction and alpha-synuclein accumulation. The lysosomal ion channel TMEM175, identified through genome-wide association studies as a risk factor, regulates the proton balance that keeps lysosomes acidic enough for their digestive enzymes to function. Even the recently characterized Commander complex has emerged as a regulator of lysosomal function and Parkinson disease risk. Each of these discoveries reinforces the same message: many independent genetic insults funnel into a single vulnerable pathway.

In Alzheimer disease, the lysosomal connection takes a somewhat different form, centered on the endocytic trafficking machinery. Enlarged endosomes packed with amyloid-beta are among the earliest pathological changes detectable in neurons of people with Alzheimer disease, appearing before amyloid plaques form. The strongest genetic link is SORL1, which encodes the receptor SORLA, a key regulator of cargo trafficking through the endolysosomal system, including trafficking of the amyloid precursor protein. Loss-of-function variants in SORL1 substantially increase Alzheimer risk, and depletion of SORLA in human neurons impairs endosomal traffic even independently of amyloidogenic processing. Other risk genes, including BIN1, PICALM and CD2AP, all participate in endocytosis and endosomal sorting, and presenilin mutations that cause familial Alzheimer disease disrupt lysosomal acidification and autophagy, although the precise role of presenilins in this process remains debated.

The lipid-carrying protein APOE adds another layer to the Alzheimer picture. The APOE4 allele, the strongest common genetic risk factor for late-onset disease, promotes the accumulation of cholesterol in lysosomes of astrocytes, impairs mitochondrial function and dampens autophagy through multiple mechanisms, including direct binding of ApoE4 to gene regulatory elements that control autophagy genes. Meanwhile, TREM2, a receptor on microglia that depends on lysosomal processing for its function, shapes how immune cells respond to amyloid plaques, although a recent clinical trial targeting TREM2 failed, underscoring how much remains to be learned about translating lysosomal biology into treatments.

Frontotemporal dementia and amyotrophic lateral sclerosis, two clinically distinct disorders with heavily overlapping genetics, supply perhaps the most direct evidence that autophagy, the cellular self-eating process that delivers cargo to lysosomes, is essential for neuronal survival. Multiple ALS and FTD genes encode proteins that regulate autophagy at different steps: TBK1 and OPTN coordinate the selective removal of damaged mitochondria; VCP and UBQLN2 participate in extracting ubiquitinated proteins for degradation; SQSTM1, also known as p62, serves as a cargo receptor that tags aggregates for autophagic clearance; and C9ORF72, the most common genetic cause of both diseases, forms a complex that regulates Rab GTPases and mTORC1 signaling at the lysosome. Mutations in CHMP2B, part of the ESCRT-III machinery that repairs ruptured lysosomal membranes, cause a distinctive form of frontotemporal dementia characterized by lysosomal storage pathology, and recent work shows that the ALS-linked proteins annexin A11 and CHMP2B act sequentially in membrane repair.

Progranulin, encoded by the GRN gene, has become a focal point for therapeutic development in frontotemporal dementia. Haploinsufficiency, meaning that carriers of a single mutated GRN copy produce only half the normal amount of the protein, causes familial FTD and produces features resembling neuronal ceroid lipofuscinosis, a classic lysosomal storage disease. Progranulin supports lysosomal homeostasis through multiple mechanisms: it promotes lysosomal acidification, acts as a chaperone for the enzyme cathepsin D, facilitates the processing of prosaposin into saposins that activate lipid-degrading enzymes, and supports glucocerebrosidase activity. The risk gene TMEM106B, which regulates lysosomal size, motility and stress responses, modifies disease penetrance in GRN mutation carriers, and strikingly, TMEM106B itself was recently discovered to form amyloid fibrils in aged brains across multiple neurodegenerative diseases. Progranulin augmentation strategies, including an antibody called latozinemab that raises progranulin levels and AAV gene therapy, are already in clinical trials, with interim results reported for the gene therapy approach.

What emerges from this synthesis is a view of neurodegeneration as, at its core, a failure of cellular housekeeping that unfolds over decades. Neurons are uniquely vulnerable because they live as long as the organism, rely heavily on long-range transport of lysosomes along axons, and generate toxic metabolic byproducts such as oxidized dopamine that further damage lysosomes. The convergence of genetic evidence from four major disease families onto the endolysosomal system suggests that therapies aimed at restoring lysosomal health, whether by enhancing enzyme activity, improving acidification, boosting autophagic flux or repairing damaged lysosomal membranes, could offer benefits that span diagnostic boundaries. With GBA1 and LRRK2 trials underway in Parkinson disease, progranulin augmentation advancing in frontotemporal dementia and lysosome-targeting small molecules in preclinical development, the humble lysosome has moved from the margins of neuroscience to the center of the search for disease-modifying treatments.

Subject of Research: Lysosomal dysfunction as a mechanism of neurodegenerative disease

Article Title: Lysosomal dysfunction in neurodegenerative disease

Article References: Brooker, S. M., Coukos, R., & Krainc, D. (2026). Lysosomal dysfunction in neurodegenerative disease. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01262-3

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01262-3

Keywords: lysosome, neurodegeneration, Parkinson disease, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, GBA1, LRRK2, autophagy, progranulin, alpha-synuclein, endolysosomal trafficking