Optimal Control with RdCVFL for Degenerating Photoreceptors.

Both the rod and cone photoreceptors, along with the retinal pigment epithelium have been experimentally and mathematically shown to work interdependently to maintain vision. Further, the theoredoxin-like rod-derived cone viability factor (RdCVF) and its long form (RdCVFL) have proven to increase photoreceptor survival in experimental results. Aerobic glycolysis is the primary source of energy production for photoreceptors and RdCVF accelerates the intake of glucose into the cones.

Restoration of Rod-Derived Metabolic and Redox Signaling to Prevent Blindness.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization.

Affinity-controlled release of rod-derived cone viability factor enhances cone photoreceptor survival.

Retinitis pigmentosa (RP) is a group of genetic diseases that results in rod photoreceptor cell degeneration, which subsequently leads to cone photoreceptor cell death, impaired vision and eventual blindness. Rod-derived cone viability factor (RdCVF) is a protein which has two isoforms: a short form (RdCVF) and a long form (RdCVFL) which act on cone photoreceptors in the retina. RdCVFL protects photoreceptors by reducing hyperoxia in the retina; however, sustained delivery of RdCVFL remains challenging.

Shedding light on myopia by studying complete congenital stationary night blindness.

Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare progressive and stationary inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in a variety of biological processes including eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signaling.

Polyglutamine-expanded ATXN7 alters a specific epigenetic signature underlying photoreceptor identity gene expression in SCA7 mouse retinopathy.

Background: Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder that primarily affects the cerebellum and retina. SCA7 is caused by a polyglutamine expansion in the ATXN7 protein, a subunit of the transcriptional coactivator SAGA that acetylates histone H3 to deposit narrow H3K9ac mark at DNA regulatory elements of active genes. Defective histone acetylation has been presented as a possible cause for gene deregulation in SCA7 mouse models.

Modulating antioxidant systems as a therapeutic approach to retinal degeneration.

The human retina is facing a big challenge of reactive oxygen species (ROS) from endogenous and exogenous sources. Excessive ROS can cause damage to DNA, lipids, and proteins, triggering abnormal redox signaling, and ultimately lead to cell death. Thus, oxidative stress has been observed in inherited retinal diseases as a common hallmark.

The Emergence of Rod-Cone Cellular Interaction.

We studied the origin of rod-derived cone viability factor (RdCVF) during evolution. In mammals, the nucleoredoxin-like 1 gene () produces a truncated thioredoxin-like protein, RdCVF, by intron retention in rod photoreceptors of the retina. This protein prevents the secondary cone degeneration in animal models of rod-cone degeneration.

The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function.

The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse (Nxnl2). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2 mouse at 2 months of age.

Mutated Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy.

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.

Assessing Photoreceptor Status in Retinal Dystrophies: From High-Resolution Imaging to Functional Vision.

Purpose: To describe the value of integrating phenotype/genotype data, disease staging, and evaluation of functional vision in patient-centered management of retinal dystrophies.

Methods: (1) Cross-sectional structure-function and retrospective longitudinal studies to assess the correlations between standard fundus autofluorescence (FAF), optical coherence tomography, visual acuity (VA), and perimetry (visual field [VF]) examinations to evaluate photoreceptor functional loss in a cohort of patients with rod-cone dystrophy (RCD); (2) flood-illumination adaptive optics (FIAO) imaging focusing on photoreceptor misalignment and orientation of outer segments; and (3) evaluation of the impact of visual impairment in daily life activities, based on functional (visual and mobility) vision assessment in a naturalistic environment in visually impaired subjects with RCD and subjects treated with Luxturna for RPE65-related Leber congenital amaurosis before and after therapy.

Results: The results of the cross-sectional transversal study showed that (1) VA and macular sensitivity were weakly correlated with the structural variables; and (2) functional impairment (VF) was correlated with reduction of anatomical markers of photoreceptor structure and increased width of autofluorescent ring.

Cone-Enriched Cultures from the Retina of Chicken Embryos to Study Rod to Cone Cellular Interactions.

Human daytime vision relies on the function of cone photoreceptors at the center of the retina, the fovea. Patients suffering from the most prevalent form of inherited retinal degeneration, retinitis pigmentosa, lose night vision because of mutation driven loss of rod photoreceptors, a phenomenon followed by a progressive loss of function and death of cones leading to blindness. Geneticists have identified many genes with mutations causing this disease, but the first mutations identified questioned the mechanisms of secondary cone degeneration and how a dominant mutation in the rhodopsin gene encoding for the visual pigment expressed exclusively in rods can trigger cone degeneration.

The role of RdCVFL in a mathematical model of photoreceptor interactions.

Recent experimental and mathematical work has shown the interdependence of the rod and cone photoreceptors with the retinal pigment epithelium in maintaining sight. Accelerated intake of glucose into the cones via the theoredoxin-like rod-derived cone viability factor (RdCVF) is needed as aerobic glycolysis is the primary source of energy production. Reactive oxidative species (ROS) result from the rod and cone metabolism and recent experimental work has shown that the long form of RdCVF (RdCVFL) helps mitigate the negative effects of ROS.

A Splice Variant in Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells.

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci.

Insulin inhibits inflammation-induced cone death in retinal detachment.

Background: Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss.

Methods: Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD.

WDR34, a candidate gene for non-syndromic rod-cone dystrophy.

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34.

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD.

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases.

The loss of cone photoreceptor function in retinitis pigmentosa (RP) severely impacts the central and daily vision and quality of life of patients affected by this disease. The loss of cones follows the degeneration of rods, in a manner independent of the causing mutations in numerous genes associated with RP. We have explored this phenomenon and proposed that the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF) encoded by the nucleoredoxin-like 1 () gene which interrupts the metabolic and redox signaling between rods and cones.

Functional Genomics of the Retina to Elucidate its Construction and Deconstruction.

The retina is the light sensitive part of the eye and nervous tissue that have been used extensively to characterize the function of the central nervous system. The retina has a central position both in fundamental biology and in the physiopathology of neurodegenerative diseases. We address the contribution of functional genomics to the understanding of retinal biology by reviewing key events in their historical perspective as an introduction to major findings that were obtained through the study of the retina using genomics, transcriptomics and proteomics.

A Mathematical Analysis of Aerobic Glycolysis Triggered by Glucose Uptake in Cones.

Patients affected by retinitis pigmentosa, an inherited retinal disease, experience a decline in vision due to photoreceptor degeneration leading to irreversible blindness. Rod-derived cone viability factor (RdCVF) is the most promising mutation-independent treatment today. To identify pathologic processes leading to secondary cone photoreceptor dysfunction triggering central vision loss of these patients, we model the stimulation by RdCVF of glucose uptake in cones and glucose metabolism by aerobic glycolysis.

Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?

The retinal pigment epithelium (RPE) forms the outer blood⁻retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE.

Mechanisms Underlying the Visual Benefit of Cell Transplantation for the Treatment of Retinal Degenerations.

The transplantation of retinal cells has been studied in animals to establish proof of its potential benefit for the treatment of blinding diseases. Photoreceptor precursors have been grafted in animal models of Mendelian-inherited retinal degenerations, and retinal pigmented epithelial cells have been used to restore visual function in animal models of age-related macular degeneration (AMD) and recently in patients. Cell therapy over corrective gene therapy in inherited retinal degeneration can overcome the genetic heterogeneity by providing one treatment for all genetic forms of the diseases.

Maintaining Cone Function in Rod-Cone Dystrophies.

Retinal degenerative diseases are a major cause of untreatable blindness due to a loss of photoreceptors. Recent advances in genetics and gene therapy for inherited retinal dystrophies (IRDs) showed that therapeutic gene transfer holds a great promise for vision restoration in people with currently incurable blinding diseases. Due to the huge genetic heterogeneity of IRDs that represents a major obstacle for gene therapy development, alternative therapeutic approaches are needed.

Cell Signaling with Extracellular Thioredoxin and Thioredoxin-Like Proteins: Insight into Their Mechanisms of Action.

Thioredoxins are small thiol-oxidoreductase enzymes that control cellular redox homeostasis. Paradoxically, human thioredoxin (TXN1) was first identified as the adult T cell leukemia-derived factor (ADF), a secreted protein. ADF has been implicated in a wide variety of cell-to-cell communication systems acting as a cytokine or a chemokine.