scholarly journals The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 784 ◽  
Author(s):  
Lars Tebbe ◽  
Mashal Kakakhel ◽  
Mustafa S. Makia ◽  
Muayyad R. Al-Ubaidi ◽  
Muna I. Naash
Keyword(s):  
Complex Formation ◽  
Mouse Models ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Fine Tuning ◽  
Current Status ◽  
Retinal Diseases ◽  
Choroidal Vasculature ◽  
And Function

Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. Although the exact role of Rom1 has not been well studied, it has been concluded that it is not necessary for disc morphogenesis but is required for fine tuning OS disc size and structure. Pathogenic mutations in PRPH2 often result in complex and multifactorial phenotypes, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium (RPE) and retinal/choroidal vasculature. The ability of Prph2 to form complexes was identified as a key requirement for the development and maintenance of OS structure and function. Studies using mouse models of pathogenic Prph2 mutations established a connection between changes in complex formation and disease phenotypes. Although progress has been made in the development of therapeutic approaches for retinal diseases in general, the highly complex interplay of functions mediated by Prph2 and the precise regulation of these complexes made it difficult, thus far, to develop a suitable Prph2-specific therapy. Here we describe the latest results obtained in Prph2-associated research and how mouse models provided new insights into the pathogenesis of its related diseases. Furthermore, we give an overview on the current status of the development of therapeutic solutions.

The photoreceptor cytoskeleton visualized

1992 ◽  
Vol 50 (1) ◽  
pp. 480-481
Author(s):  
Beth Burnside
Keyword(s):  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Polarization ◽  
Synaptic Proteins ◽  
Cell Functions ◽  
Vertebrate Photoreceptor ◽  
Numerous Cell ◽  
Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

scholarly journals Metabolism in the Zebrafish Retina

2021 ◽  
Vol 9 (1) ◽  
pp. 10
Author(s):  
Natalia Jaroszynska ◽  
Philippa Harding ◽  
Mariya Moosajee
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Therapeutic Approaches ◽  
Retinal Photoreceptors ◽  
Sufficient Energy ◽  
Metabolic Products ◽  
Sight Loss ◽  
Choroidal Vasculature ◽  
The Brain

Retinal photoreceptors are amongst the most metabolically active cells in the body, consuming more glucose as a metabolic substrate than even the brain. This ensures that there is sufficient energy to establish and maintain photoreceptor functions during and after their differentiation. Such high dependence on glucose metabolism is conserved across vertebrates, including zebrafish from early larval through to adult retinal stages. As the zebrafish retina develops rapidly, reaching an adult-like structure by 72 hours post fertilisation, zebrafish larvae can be used to study metabolism not only during retinogenesis, but also in functionally mature retinae. The interplay between rod and cone photoreceptors and the neighbouring retinal pigment epithelium (RPE) cells establishes a metabolic ecosystem that provides essential control of their individual functions, overall maintaining healthy vision. The RPE facilitates efficient supply of glucose from the choroidal vasculature to the photoreceptors, which produce metabolic products that in turn fuel RPE metabolism. Many inherited retinal diseases (IRDs) result in photoreceptor degeneration, either directly arising from photoreceptor-specific mutations or secondary to RPE loss, leading to sight loss. Evidence from a number of vertebrate studies suggests that the imbalance of the metabolic ecosystem in the outer retina contributes to metabolic failure and disease pathogenesis. The use of larval zebrafish mutants with disease-specific mutations that mirror those seen in human patients allows us to uncover mechanisms of such dysregulation and disease pathology with progression from embryonic to adult stages, as well as providing a means of testing novel therapeutic approaches.

scholarly journals Retinal Pigment Epithelium Expressed Toll-like Receptors and Their Potential Role in Age-Related Macular Degeneration

2021 ◽  
Vol 22 (16) ◽  
pp. 8387
Author(s):  
Alexa Klettner ◽  
Johann Roider
Keyword(s):  
Retinal Pigment Epithelium ◽  
Inflammatory Response ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Current Status ◽  
Toll Like Receptors ◽  
Cell Degeneration ◽  
Age Related

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- or danger-associated molecular pattern. The involvement of TLR activation in AMD is so far not understood. (2) Methods: We performed a systematic literature research, consulting the National Library of Medicine (PubMed). (3) Results: We identified 106 studies, of which 54 were included in this review. Based on these studies, the current status of TLR in AMD, the effects of TLR in RPE activation and of the interaction of TLR activated RPE with monocytic cells are given, and the potential of TLR activation in RPE as part of the AMD development is discussed. (4) Conclusion: The activation of TLR2, -3, and -4 induces a profound pro-inflammatory response in the RPE that may contribute to (long-term) inflammation by induction of pro-inflammatory cytokines, reducing RPE function and causing RPE cell degeneration, thereby potentially constantly providing new TLR ligands, which could perpetuate and, in the long run, exacerbate the inflammatory response, which may contribute to AMD development. Furthermore, the combined activation of RPE and microglia may exacerbate neurotoxic effects.

scholarly journals Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium

2021 ◽  
Vol 22 (17) ◽  
pp. 9618
Author(s):  
Jérémie Canonica ◽  
Min Zhao ◽  
Tatiana Favez ◽  
Emmanuelle Gelizé ◽  
Laurent Jonet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Retinal Pigment Epithelium ◽  
Barrier Function ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Diseases ◽  
Mesenchymal Transition ◽  
Rpe Cells ◽  
Pathway Activation ◽  
And Migration

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.

Changes of outer retinal thickness with increasing age in normal eyes

2020 ◽  
Vol 1 (2) ◽  
pp. 108-112
Author(s):  
Zi-Jing Li ◽  
◽  
Jian-Hui Xiao ◽  
Peng Zeng ◽  
Xiang Gao ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Outer Segment ◽  
Retinal Thickness ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Layer ◽  
External Limiting Membrane ◽  
The Cost ◽  
The Relationship ◽  
Sd Oct

AIM: To comprehensively investigate the relationship between outer retinal layer thickness and age in normal eyes. METHODS: One hundred normal eyes of 100 subjects who underwent spectral-domain optical coherence tomography (SD-OCT) were included in this retrospective study. The distances between the external limiting membrane (ELM) line and the photoreceptor inner segment/outer segment (IS/OS) line (ELM-IS/OS), the IS/OS line and the cone outer segment tips (COST) line (IS/OS-COST), the COST line and the retinal pigment epithelium (RPE) complex (COST-RPE) and the full retinal thickness (RT) were measured at the fovea and on four quarters. The relationship between thickness and age or sex was then analysed. CONCLUSION: In normal eyes, the RT thickness on the nasal quarter and the ELM-IS/OS thickness were significantly and negatively correlated with age. The IS/OS-COST and COST-RPE thicknesses were not significantly correlated with age or sex.

Impaired visual thresholds in hypopigmented animals

1991 ◽  
Vol 6 (6) ◽  
pp. 577-585 ◽  
Author(s):  
Grant W. Balkema ◽  
Ursula C. Dräger
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Visual Sensitivity ◽  
The Body ◽  
Melanin Pigmentation ◽  
Similar Threshold ◽  
The Mean ◽  
Single Unit Recordings ◽  
The Difference ◽  
And Function

AbstractOcular hypopigmentation is associated with neurological defects in structure and function. This paper investigates the ab/Fute visual thresholds in dark-adapted hypopigmented animals compared to their normally pigmented controls. Here we asked (1) whether the threshold elevation found in hypopigmented animals is a general consequence of the reduction in melanin content; (2) if so, which melanin components in the eye are likely to influence visual thresholds; and (3) whether similar threshold defects can be detected in orders other than rodents. By single-unit recordings from the superior colliculus, we compared incremental thresholds of normal black mice of the C57BL/6J strain to hypopigmented mutants: beige (bg/bg), pale ear (ep/ep), and albino (c2J/c2J) mice, three mutants in which melanin pigment throughout the body is affected; and Steel (Sl/Sld) and dorninant-spotting/W-mice (W/Wν), two mutants with normal pigmentation in the retinal pigment epithelium (RPE) but without any melanin in the choroid or the rest of the body. We found that all mutants had elevated thresholds that varied with the reduction in melanin. The albinos were 25 times less sensitive than black mice, pale ear mice 20 times, beige mice 11 times, and Steel and W-mice 5 times. The mean thresholds of dark-adapted black mice were 0.008 cd/m2. Recordings from rabbits showed a similar impairment of visual sensitivity: incremental thresholds were elevated 40 times in New Zealand-White albino rabbits (0.0008 cd/m2) compared to Dutch-Belted pigmented controls (0.00002 cd/m2). Previously, it has been shown that hypopigmented rats have elevated dark-adapted thresholds compared to pigmented controls (Balkema, 1988); here we show that the difference between hypopigmented rats and pigmented controls is not caused by insufficient dark adaptation or excessive variability in the results from albino mutant compared to its control.Mutations that cause a reduction of ocular melanin pigmentation, regardless of the gene mutated or the mechanism underlying the hypopigmentation, are accompanied by an elevation in visual thresholds which is roughly proportional to the reduction in melanin. Melanin both in the RPE and choroid exert an effect on visual thresholds. Like the defects in optic nerve crossing and eye movements, the effect of melanin on visual thresholds is not restricted to rodents, but is seen in other orders. The threshold impairment in hypopigmented animals cannot be explained by impaired photoprotection, but it points to another physiological action of melanin.

Normative pattern and determinants of outer retinal thickness in an Asian population: the Singapore Epidemiology of Eye Diseases Study

2019 ◽  
Vol 103 (10) ◽  
pp. 1406-1412 ◽  
Author(s):  
Wei Dai ◽  
Yih-Chung Tham ◽  
Miao-Li Chee ◽  
Shivani Majithia ◽  
Nicholas Y Q Tan ◽  
...  
Keyword(s):  
Retinal Thickness ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Plexiform Layer ◽  
Asian Population ◽  
Final Analysis ◽  
Population Based ◽  
Eye Diseases ◽  
Retinal Diseases ◽  
Sd Oct

Background/aimsTo evaluate the distribution and determinants of outer retinal thickness in eyes without retinal diseases, using spectral-domain optical coherence tomography (SD-OCT).MethodsParticipants were recruited from the Singapore Epidemiology of Eye Diseases Study, a population-based study among Chinese, Malays and Indians in Singapore. A total of 5333 participants underwent SD-OCT imaging in which a 6×6 mm2 measurement area centred at the fovea. Outer retinal thickness was defined as the distance from the outer plexiform layer to the retinal pigment epithelium layer boundary.Results7444 eyes from 4454 participants were included in final analysis. Of them, mean age was 58.4 years (SD 8.3), and 2294 (51.5%) were women. Women (121.0±8.1 µm) had thinner average outer retinal thickness than men (125.6±8.2 µm) (p<0.001). Malays (121.4±8.7 µm) had thinner average outer retinal thickness than Indians (124.3±8.6 µm) and Chinese (123.7±7.9 µm) (both p<0.001). In multivariable models, thinner average outer retinal thickness was associated with older age (per decade, β=−1.02, p<0.001), hypertension (β=−0.59, p=0.029), diabetes (β=−0.73, p=0.013), chronic kidney disease (β=−1.25, p=0.017), longer axial length (per mm, β=−0.76, p<0.001), flatter corneal curvature (per mm, β=−2.00, p<0.001) and higher signal strength (β=−1.46, p<0.001).ConclusionIn this large sample of Asian population, we provided normative SD-OCT data on outer retinal thickness in eyes without retinal diseases. Women had thinner outer retina than men. For the first time, these findings provide fundamental knowledge on normative profile of outer retinal thickness in Asians.

scholarly journals Regulation of phagolysosomal activity by miR-204 critically influences structure and function of retinal pigment epithelium/retina

2019 ◽  
Vol 28 (20) ◽  
pp. 3355-3368 ◽  
Author(s):  
Congxiao Zhang ◽  
Kiyoharu J Miyagishima ◽  
Lijin Dong ◽  
Aaron Rising ◽  
Malika Nimmagadda ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Primary Cultures ◽  
Structure And Function ◽  
Apical Surface ◽  
Altered Expression ◽  
And Function ◽  
The Impact

Abstract MicroRNA-204 (miR-204) is expressed in pulmonary, renal, mammary and eye tissue, and its reduction can result in multiple diseases including cancer. We first generated miR-204−/− mice to study the impact of miR-204 loss on retinal and retinal pigment epithelium (RPE) structure and function. The RPE is fundamentally important for maintaining the health and integrity of the retinal photoreceptors. miR-204−/− eyes evidenced areas of hyper-autofluorescence and defective photoreceptor digestion, along with increased microglia migration to the RPE. Migratory Iba1+ microglial cells were localized to the RPE apical surface where they participated in the phagocytosis of photoreceptor outer segments (POSs) and contributed to a persistent build-up of rhodopsin. These structural, molecular and cellular outcomes were accompanied by decreased light-evoked electrical responses from the retina and RPE. In parallel experiments, we suppressed miR-204 expression in primary cultures of human RPE using anti-miR-204. In vitro suppression of miR-204 in human RPE similarly showed abnormal POS clearance and altered expression of autophagy-related proteins and Rab22a, a regulator of endosome maturation. Together, these in vitro and in vivo experiments suggest that the normally high levels of miR-204 in RPE can mitigate disease onset by preventing generation of oxidative stress and inflammation originating from intracellular accumulation of undigested photoreactive POS lipids. More generally, these results implicate RPE miR-204-mediated regulation of autophagy and endolysosomal interaction as a critical determinant of normal RPE/retina structure and function.

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