Sickle cell disease is best known for the crises it inflicts on the blood, lungs and bones, but one of its most insidious targets is the eye. Sickle cell retinopathy, the leading ocular complication of the disease, develops silently as rigid, sickle-shaped red blood cells clog the retina’s delicate microvasculature, starving the tissue of oxygen. In its proliferative form, fragile new vessels sprout in response to that hypoxia, and when they rupture they can trigger vitreous hemorrhage and retinal detachment, leaving 10 to 20 percent of affected eyes with permanent vision loss. Yet the molecular events that unfold before any of this becomes visible have remained largely uncharted. A new study published in Experimental Biology and Medicine offers the first comprehensive proteomic portrait of the sickle cell retina, and its findings suggest that the disease’s earliest damage may be metabolic and photic rather than vascular.
Researchers at the State University of Campinas in Brazil, working with collaborators in Hungary, Switzerland, France and São Paulo, turned to the Townes HbSS mouse, a humanized model of sickle cell anemia in which the animals carry the same single-point mutation in the beta-globin gene that defines the human disease. That mutation, a substitution of valine for glutamic acid at the sixth codon, causes hemoglobin S to polymerize when deoxygenated, deforming red cells into their characteristic crescent shape. The resulting rigidity and membrane alterations drive hemolysis, endothelial dysfunction, vaso-occlusion and ischemia throughout the body, and the retina, with its exceptionally high metabolic demand, is particularly vulnerable to the consequences.
To confirm that the model faithfully reproduced the human condition, the team first characterized the animals’ blood. Compared with C57BL/6J controls, the Townes HbSS mice showed reductions of roughly 58 percent in erythrocyte count, 52 percent in hematocrit and 46 percent in hemoglobin concentration, alongside dramatic elevations in reticulocytes and white blood cells. Markers of hemolysis told a similar story: total, direct and indirect bilirubin levels were all massively increased, consistent with the ongoing destruction of red cells that characterizes sickle cell anemia. These hematological and metabolic signatures confirmed that the experimental group carried the disease phenotype before any retinal analysis began.
The researchers then probed retinal function using electroretinography, a technique that measures the electrical potentials generated between the cornea and the retina in response to flashes of light of varying intensity. Under dark-adapted conditions, which isolate rod photoreceptor activity, the sickle cell mice produced a-wave amplitudes significantly smaller than controls at the highest light intensity tested, and their implicit times were shortened at an intermediate flash strength. Under light-adapted conditions, which emphasize cone and bipolar cell responses, the b-wave implicit time was prolonged in the diseased animals, indicating a delayed signal in the bipolar cell layer. Perhaps most strikingly, the oscillatory potentials, small rhythmic wavelets superimposed on the b-wave that are thought to reflect inner retinal amacrine cell activity, were reduced in amplitude at maximum light intensity, hinting at early damage to the inner retina before gross structural changes appear.
Histological examination of stained retinal sections reinforced this picture of degeneration. Both the sickle cell mice and the aged controls showed some disorganization of the outer nuclear layer, where photoreceptor cell bodies reside, but the Townes HbSS animals also displayed discrete alterations in the inner nuclear layer, suggesting a pathophysiological process distinct from simple aging. Blood vessels were additionally observed within the ganglion cell layer of the sickle cell retinas, a finding the authors interpret as consistent with the vascular remodeling that accompanies the disease. Because the control strain is known to undergo gradual photoreceptor degeneration beginning around six months of age, the team attributes the inner retinal changes in the sickle cell mice specifically to the vaso-occlusion and hypoxia of the disease rather than to time alone.
The centerpiece of the study, however, is the proteomic analysis. Using label-free quantification on an LTQ Orbitrap Velos mass spectrometer coupled to nanoflow liquid chromatography, the researchers mapped the retinal proteome across pooled samples from five sickle cell mice and seven controls. The analysis identified 2,248 proteins in total, of which 163 were detected exclusively in control retinas and 43 only in the sickle cell group. After applying a nominal significance threshold, 268 proteins emerged as differentially expressed: 63 upregulated and 205 downregulated in the diseased retinas. While no individual protein survived correction for false discovery rate, the pattern of change was far from random, and functional enrichment analysis revealed a coherent molecular story.
Among the downregulated proteins, the most heavily enriched pathways were phototransduction, the citric acid cycle and oxidative phosphorylation, the mitochondrial machinery that generates most of the cell’s ATP. Among the upregulated proteins, the enriched pathways included glycolysis, gluconeogenesis and signaling through hypoxia-inducible factor 1, the master transcriptional regulator of the cellular response to low oxygen. This reciprocal pattern, a collapse of oxygen-dependent energy production paired with an activation of hypoxia-adaptive programs, mirrors what has been observed in other proliferative retinopathies such as retinopathy of prematurity, where independent work has shown that mitochondrial respiration declines at the peak of neovascularization and that supplying metabolic substrates can suppress pathological angiogenesis.
Within the phototransduction pathway, several proteins stood out. The Pde6 family, comprising the alpha, beta and gamma subunits of rod phosphodiesterase, was downregulated, as were Cnga1, the alpha subunit of the cyclic nucleotide-gated channel that carries sodium and calcium into the photoreceptor outer segment, and Slc24a1, a sodium-calcium-potassium exchanger that regulates calcium clearance and photoreceptor recovery after light exposure. Mutations in these same genes are known causes of retinitis pigmentosa and congenital stationary night blindness in humans, disorders characterized by progressive photoreceptor degeneration. To verify that the protein-level findings reflected genuine transcriptional changes, the researchers performed quantitative reverse transcription PCR on selected targets, confirming that both Cnga1 and Slc24a1 messenger RNA were also reduced in the sickle cell retinas, in agreement with the proteomic data.
The convergence of proteomic and transcriptomic evidence on the phototransduction cascade carries particular weight because it suggests that the molecular machinery for converting light into neural signals is being dismantled early in the disease process, before the morphological and functional deficits become pronounced. In a single-cell RNA sequencing study of a retinitis pigmentosa model, downregulation of Pde6g, Cnga1 and Slc24a1 was interpreted as a signature of early rod degeneration that precedes clinical manifestations. The sickle cell retina appears to be following a similar trajectory, driven not by genetic mutation of the photoreceptors themselves but by the hypoxic and ischemic environment created by vaso-occlusion in the microvasculature that supplies them.
The clinical implications are sobering. Current treatments for proliferative sickle cell retinopathy, including laser photocoagulation, intravitreal anti-VEGF injections and vitrectomy for advanced complications, are borrowed from other proliferative retinopathies without dedicated prospective trials in the sickle cell context. While anti-VEGF therapy has shown benefit in regressing seafan vessels and improving vision, recent work in a mouse model of retinal vascular disease found that chronic VEGF inhibition failed to rescue the expression of phototransduction-related genes or prevent photoreceptor loss, raising the possibility that vascular-targeted approaches alone may not address the full spectrum of retinal damage in sickle cell disease. By identifying the metabolic and phototransduction pathways that are compromised before overt structural breakdown, this proteomic study provides a molecular foundation for developing biomarkers that could detect sickle cell retinopathy earlier and for designing mechanism-based therapies that protect photoreceptors directly rather than merely pruning abnormal vessels. The authors acknowledge limitations, including the use of the C57BL/6J strain as controls rather than the ideal Townes HbAA comparator and the absence of retinal flat-mount analysis for angiogenesis quantification, but the molecular landscape they have charted offers a starting point for a field that has long lacked one.
Subject of Research: Proteomic analysis of retinal molecular pathways in a humanized mouse model of sickle cell retinopathy
Article Title: Sickle cell retinopathy molecular investigation through proteomic analysis of Townes HbSS mice retinas
Article References: de Castro, J. N. P., Monte, A. R. C., de Oliveira, A. C. R., Acacio, J. D., Rodrigues, T. A. R., Barboni, M. T. S., Liber, A. M. P., Bonci, D. M. O., Ventura, D. F., Costa, F. F., Camargo, A. C. L., & de Melo, M. B. (2026). Sickle cell retinopathy molecular investigation through proteomic analysis of Townes HbSS mice retinas. Experimental Biology and Medicine, 251, Article 11228. https://doi.org/10.3389/ebm.2026.11228
Image Credits: AI Generated
Keywords: sickle cell retinopathy, sickle cell disease, proteomics, Townes HbSS mice, phototransduction, oxidative phosphorylation, hypoxia, retinal degeneration, anti-VEGF, electroretinography, biomarkers, retina
News Source: Drew Townsend. (October 15, 2026). Proteomic Map of Sickle Cell Retinopathy Reveals Early Photoreceptor Breakdown in Humanized Mice. Scienmag.
