Biology subjects

Corydon, T.

Publications and source records attributed to Corydon, T..

3 recordsLinked to original sources

bioRxiv2026

Megalin deficiency perturbs retinal homeostasis and impairs cathepsin D processing and phagosome-lysosome maturation in the retinal pigment epithelium

The multiligand endocytic receptor, megalin (LRP2), is expressed in the retinal pigment epithelium (RPE) and patients lacking the receptor develop high myopia. Despite its established role in retinal development, the contribution of megalin to retinal homeostasis in the normally developed/mature eye remains poorly understood. Here, we investigated megalin function using an inducible knockout mouse (KO) model and human iPSC-derived RPE with megalin knockdown (KD) to distinguish post-developmental homeostatic functions from developmental effects. In vivo, megalin ablation caused progressive retinal degeneration and visual impairment, with morphological abnormalities in the RPE but no changes in myopia-associated ocular phenotypes including axial length and intraocular pressure. Proteomic profiling of megalin-KO RPE revealed reduction of autophagy-related proteins. In line with this, megalin deficiency was associated with accumulation of pro-cathepsin D, and perturbed rhodopsin turnover. This was supported in vitro, where trafficking of photoreceptor outer segment (POS) containing phagosomes to lysosomes was reduced, suggesting disturbed phagosome maturation. Megalin KD did not measurably impair initial uptake of POS discs, but delayed rhodopsin degradation, indicating defective post-ingestion processing. Together, these findings establish megalin as a key regulator of retinal homeostasis in the mature eye by controlling phagosome-lysosome fusion in the RPE and suggest that megalin dysfunction contributes to slowly progressive retinal degeneration. This positions megalin as a potential therapeutic target in lysosomal degenerative diseases in the retina.

Cell Biology↗

bioRxiv2025

P2Y2 receptors are essential for hepatic clearance ofuropathogenic E. coli in a murine sepsis model

Urosepsis is a life-threatening condition most frequently caused by E. coli expressing important virulence factors, including -haemolysin (HlyA). The pore-forming exotoxin HlyA releases ATP upon its insertion into cellular membranes, and the majority of the biological effects of HlyA are mediated through ATP-dependent P2-receptor activation, including the HlyA-mediated thrombocyte activation. We have recently shown that uropathogenic E. coli (UPEC) bind to thrombocytes immediately after entering the blood, and the following hepatic clearance leads to early thrombocytopenia during bacteraemia. Here, we demonstrate that P2Y2-deficient mice had markedly shorter survival (LD50 of 185 minutes) compared to wildtype (340 minutes), a response paralleled in mice infused with the P2Y2 receptor antagonist AR-C118925XX. The P2Y2-/- mice exhibited a blunted sepsis-induced thrombocytopenia compared to wildtype and sepsis-induced reduction in mature neutrophils in the blood. Strikingly, the P2Y2-deficient mice had inadequate hepatic clearance of UPEC, resulting in the accumulation of bacteria in the lungs, while thrombocytes were mainly sequestered in the kidneys. Hence, it is likely that the insufficient hepatic elimination of UPEC is responsible for the reduced survival in the P2Y2-/- mice. Taken together, we show that the lack of functional P2Y2 receptors is essential for fast and proper hepatic clearance of UPEC and the survival time during urosepsis. Moreover, the data support the notion that an early reduction in circulating thrombocytes is important for a relevant host response to acute bacteraemia.

physiology↗

bioRxiv2025

Platelet-dependent clearance of uropathogenic Escherichia coli directly drives sepsis-induced thrombocytopenia in a mouse model

Thrombocytopenia is a distinct negative prognostic marker in sepsis, a trait associated with the procoagulatory state of severe infection. However, thrombocytes have transcended to encompass a modulatory role in the immune response and as pathogen scavengers. In a murine model of urosepsis, we observed a substantial drop (40%) in circulating thrombocytes already 30 minutes after the introduction of uropathogenic Escherichia coli (UPEC) and a concomitant transient increase in both platelet factor 4 release and thrombin-antithrombin complexes. This reduction in thrombocytes was timely associated with a reduction in circulating UPEC. By imaging flow cytometry, we visualized that eGFP-expressing UPEC was instantly bound to circulating thrombocytes, leading to the immediate removal of thrombocyte-UPEC complexes and a 95% reduction in bacterial load within 10 minutes. We demonstrate that thrombocyte-UPEC complexes are cleared primarily through the liver, engaging the sinusoidal endothelial cells. The majority of the UPEC are recovered in the liver, with minimal contribution from intravascular bacterial damage or lysis. The thrombocyte-dependent clearance system has a maximal capacity, and overload markedly challenges the intravascular UPEC-clearance. The data strongly suggest that circulating thrombocytes constitute the most important cell type for fast scavenging and clearance of invading bacteria during urosepsis and demonstrate that thrombocytopenia can be a direct function of bacteremia with UPEC.

physiology↗