scholarly journals Development of Retinal Degenerative Model Using Lead Acetate (PbAc) in Zebrafish: Morphological and Behavioral Aspects

2021 ◽  
Author(s):  
Vincy Garg ◽  
Ravneet Kaur
Keyword(s):  
Retinal Degeneration ◽  
Lead Acetate ◽  
Photoreceptor Cells ◽  
Ultrastructural Level ◽  
Retinal Cell ◽  
Visual Response ◽  
Photoreceptor Layer ◽  
Rod Cells ◽  
Degenerative Disorders ◽  
Pigmented Epithelium

Abstract Lead intoxication reduces cGMP phosphodiesterase activity and enhances the influx of Ca2+ in photoreceptor cells that trigger ATP loss. Thus, releasing proapoptotic factors and activating caspase cascade results in retinal cell apoptosis. In the current study, lead acetate (PbAc) induced retinal degenerative model which mimics ocular degenerative disorders like macular degeneration and retinitis pigmentosa. Qualitative and quantitative analysis of retinal histology, with dose and time response parameters, showed 0.08mg/L concentration for 15 days of treatment was the appropriate dose to develop the retinal degeneration model. Its intoxication affected the photoreceptor cells thus contributing to above mentioned disorders. At an ultrastructural level, it was observed that PbAc induce retinal degeneration by damaging outer and inner segments of the photoreceptors especially the rod cells. Escape response behavior also showed a significant decrease in visual response to changing contrasts. Thus, PbAc was inducing degeneration of retina between pigmented epithelium and photoreceptor layer for further retinal regenerative studies. Lead intoxication reduces cGMP phosphodiesterase activity and enhances the influx of Ca2+ in photoreceptor cells that trigger ATP loss. Thus, releasing proapoptotic factors and activating caspase cascade results in retinal cell apoptosis. In the current study, lead acetate (PbAc) induced retinal degenerative model which mimics ocular degenerative disorders like macular degeneration and retinitis pigmentosa. Qualitative and quantitative analysis of retinal histology, with dose and time response parameters, showed 0.08mg/L concentration for 15 days of treatment was the appropriate dose to develop the retinal degeneration model. Its intoxication affected the photoreceptor cells thus contributing to above mentioned disorders. At an ultrastructural level, it was observed that PbAc induce retinal degeneration by damaging outer and inner segments of the photoreceptors especially the rod cells. Escape response behavior also showed a significant decrease in visual response to changing contrasts. Thus, PbAc was inducing degeneration of retina between pigmented epithelium and photoreceptor layer for further retinal regenerative studies.

scholarly journals Arachidonic acid supplementation during gestational, lactational and post-weaning periods prevents retinal degeneration induced in a rodent model

2012 ◽  
Vol 109 (8) ◽  
pp. 1424-1432 ◽  
Author(s):  
Katsuhiko Yoshizawa ◽  
Tomo Sasaki ◽  
Maki Kuro ◽  
Norihisa Uehara ◽  
Hideho Takada ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Retinal Degeneration ◽  
Outer Nuclear Layer ◽  
Basal Diet ◽  
Photoreceptor Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Retinal Damage ◽  
Lewis Rats ◽  
Photoreceptor Layer ◽  
Central Retina

Fatty acids and their derivatives play a role in the response to retinal injury. The effects of dietary arachidonic acid (AA) supplementation on N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was investigated in young Lewis rats during the gestational, lactational and post-weaning periods. Dams were fed 0·1, 0·5 or 2·0 % AA diets or a basal ( < 0·01 % AA) diet. On postnatal day 21 (at weaning), male pups received a single intraperitoneal injection of 50 mg MNU/kg or vehicle, and were fed the same diet as their mother for 7 d. Retinal apoptosis was analysed by the terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labelling (TUNEL) assay 24 h after the MNU treatment, and retinal morphology was examined 7 d post-MNU. Histologically, all rats that received MNU and were fed the basal and 0·1 % AA diets developed retinal degeneration characterised by the loss of photoreceptor cells (disappearance of the outer nuclear layer and the photoreceptor layer) in the central retina. The 0·5 and 2·0 % AA diets rescued rats from retinal damage. Morphometrically, in parallel with the AA dose (0·5 and 2·0 % AA), the photoreceptor ratio significantly increased and the retinal damage ratio decreased in the central retina, compared with the corresponding ratios in basal diet-fed rats. In parallel with the increase in serum and retinal AA levels and the AA:DHA ratio, the apoptotic index in the central retina was dose-dependently decreased in rats fed the 0·5 and 2·0 % AA diets. In conclusion, an AA-rich diet during the gestation, lactation and post-weaning periods rescued young Lewis rats from MNU-induced retinal degeneration via the inhibition of photoreceptor apoptosis. Therefore, an AA-enriched diet in the prenatal and postnatal periods may be an important strategy to suppress the degree of photoreceptor injury in humans.

scholarly journals Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yevgeniya Atiskova ◽  
Susanne Bartsch ◽  
Tatyana Danyukova ◽  
Elke Becker ◽  
Christian Hagel ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Lysosomal Enzyme ◽  
Ganglion Cells ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Photoreceptor Cells ◽  
Cell Types ◽  
Significant Loss ◽  
Retinal Cell ◽  
Depth Analysis ◽  
Palmitoyl Protein Thioesterase

Abstract Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures, and retinal degeneration ultimately resulting in blindness. Here, we performed an in-depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition. Reactive astrogliosis and microgliosis were evident in mutant retinas prior to the onset of retinal cell loss. Progressive accumulation of storage material, a pronounced dysregulation of various lysosomal proteins, and accumulation of sequestosome/p62-positive aggregates in the inner nuclear layer also preceded retinal degeneration. At advanced stages of the disease, the mutant retina was characterized by a significant loss of ganglion cells, rod and cone photoreceptor cells, and rod and cone bipolar cells. Results demonstrate that PPT1 dysfunction results in early-onset pathological alterations in the mutant retina, followed by a progressive degeneration of various retinal cell types at relatively late stages of the disease. Data will serve as a reference for future work aimed at developing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease.

scholarly journals Conditional Loss of the Exocyst Component exoc5 in Retinal Pigment Epithelium (RPE) Results in RPE Dysfunction, Photo-Receptor Cell Degeneration, and Decreased Visual Function.

2021 ◽  
Author(s):  
Bärbel Rohrer ◽  
Elisabeth Obert ◽  
Yujing Dang ◽  
Yanhui Su ◽  
Xiaofeng Zuo ◽  
...  
Keyword(s):  
Visual Function ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Retinal Cell ◽  
Cell Degeneration ◽  
Genetic Ablation ◽  
Pigmented Epithelium ◽  
Cone Opsins ◽  
Retinal Thinning

To characterize the mechanisms by which the highly-conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on exoc5 (aka sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific Exoc5 knockout mice. Exoc5 is present in both the non-pigmented epithelium of the ciliary body and in the RPE. In this study we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if loss of visual function is induced by postnatal RPE Exoc5-deficiency. Exoc5-/- zebrafish showed smaller eyes, with decreased number of melanocytes in the RPE and shorter photoreceptor outer segments. At 3.5 days post fertilization, loss of rod and cone opsins were observed in zebrafish Tg:exoc5 mutants. Mice with postnatal RPE-specific loss of Exoc5 showed retinal thinning associated with compromised visual function, and loss of visual photoreceptor pigments. This retinal phenotype in Exoc5-/- mice was present at 20-weeks, and the phenotype was more severe at 27-weeks, indicating progressive disease phenotype. We previously showed that the exocyst is necessary for photoreceptor ciliogenesis and retinal development. Here, we report that exoc5 mutant zebrafish and mice with RPE-specific genetic ablation of Exoc5 develop abnormal RPE pigmentation, resulting in retinal cell dystrophy and loss of visual pigments associated with compromised vision. As RPE cells are &ldquo;downstream&rdquo; of photoreceptor cells in the visual process, these data suggest exocyst-mediated retrograde communication and dependence between the RPE and photoreceptors.

scholarly journals SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration

2020 ◽  
Vol 3 (5) ◽  
pp. e201900618 ◽  
Author(s):  
Ema Ozaki ◽  
Luke Gibbons ◽  
Nuno GB Neto ◽  
Paul Kenna ◽  
Michael Carty ◽  
...  
Keyword(s):  
Cell Survival ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Neuronal Cell ◽  
Photoreceptor Cells ◽  
Cone Photoreceptor ◽  
Double Knockout ◽  
Cell Degeneration ◽  
Photoreceptor Layer ◽  
Dependent Cell

Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho−/−sarm1−/− double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho−/−) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.

scholarly journals Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1033
Author(s):  
Lorena Olivares-González ◽  
Sheyla Velasco ◽  
Isabel Campillo ◽  
David Salom ◽  
Emilio González-García ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Degeneration ◽  
Antioxidant Properties ◽  
Photoreceptor Cells ◽  
Redox Status ◽  
Inherited Retinal Dystrophies ◽  
Stress Markers ◽  
Retinal Dystrophies ◽  
Progressive Degeneration ◽  
Light Stimuli

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. Methods: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. Results: NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. Conclusions: NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.

Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation

2021 ◽  
Vol 118 (43) ◽  
pp. e2100566118
Author(s):  
Oksana Kutsyr ◽  
Agustina Noailles ◽  
Natalia Martínez-Gil ◽  
Lucía Maestre-Carballa ◽  
Manuel Martinez-Garcia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Gut Microbiome ◽  
Cell Activation ◽  
High Fat ◽  
Short Term ◽  
Oxidative Markers ◽  
Degenerative Disorders ◽  
Inflammatory State

A high-fat diet (HFD) can induce hyperglycemia and metabolic syndromes that, in turn, can trigger visual impairment. To evaluate the acute effects of HFD feeding on retinal degeneration, we assessed retinal function and morphology, inflammatory state, oxidative stress, and gut microbiome in dystrophic retinal degeneration 10 (rd10) mice, a model of retinitis pigmentosa, fed an HFD for 2 to 3 wk. Short-term HFD feeding impaired retinal responsiveness and visual acuity and enhanced photoreceptor degeneration, microglial cell activation, and Müller cell gliosis. HFD consumption also triggered the expression of inflammatory and oxidative markers in rd10 retinas. Finally, an HFD caused gut microbiome dysbiosis, increasing the abundance of potentially proinflammatory bacteria. Thus, HFD feeding drives the pathological processes of retinal degeneration by promoting oxidative stress and activating inflammatory-related pathways. Our findings suggest that consumption of an HFD could accelerate the progression of the disease in patients with retinal degenerative disorders.

scholarly journals Overexpression of MiR-183/96/182 Triggers Retina-Like Fate in Human Bone Marrow-Derived Mesenchymal Stem Cells (hBMSCs) in Culture

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Mohammad-Reza Mahmoudian-Sani ◽  
Fatemeh Forouzanfar ◽  
Samira Asgharzade ◽  
Nilufar Ghorbani
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Retinal Degeneration ◽  
Photoreceptor Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Efficient Treatment ◽  
Qrt Pcr

Retinal degeneration is considered as a condition ensued by different blinding disorders such as retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy, which can cause loss of photoreceptor cells and also lead to significant vision deficiencies. Although there is no efficient treatment in this domain, transplantation of stem cells has been regarded as a therapeutic approach for retinal degeneration. Thus, the purpose of this study was to analyze the potential of human bone marrow-derived mesenchymal stem cells (hBMSCs) to differentiate into photoreceptor cells via transfection of microRNA (miRNA) in vitro for regenerative medicine purposes. To this end, miR-183/96/182 cluster was transfected into hBMSCs; then, qRT-PCR was performed to measure the expression levels of miR-183/96/182 cluster and some retina-specific neuronal genes such as OTX2, NRL, PKCα, and recoverin. CRX and rhodopsin (RHO) levels were also measured through qRT-PCR and immunocytochemistry, and subsequently, cellular change morphology was detected. The findings showed no changes in the morphology of the given cells, and the expression of the neuroretinal genes such as OTX2, NRL, and PKCα. Moreover, recoverin was upregulated upon miR-183/-96/-182 overexpression in cultured hBMSCs. Ectopic overexpression of the miR-183 cluster could further increase the expression of CRX and RHO at the messenger RNA (mRNA) and protein levels. Furthermore, the data indicated that the miR-183 cluster could serve as a crucial function in photoreceptor cell differentiation. In fact, miRNAs could be assumed as potential targets to exploit silent neuronal differentiation. Ultimately, it was suggested that in vitro overexpression of miR-183 cluster could trigger reprogramming of the hBMSCs to retinal neuron fate, especially photoreceptor cells.

scholarly journals ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eun-Jin Lee ◽  
Priscilla Chan ◽  
Leon Chea ◽  
Kyle Kim ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Mrna Levels ◽  
Photoreceptor Layer ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractRetinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho+/P23H) mice. Significantly increased rhodopsin protein levels were found in Atf6−/−Rho+/P23H retinas compared to Atf6+/−Rho+/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6−/−Rho+/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho+/P23H mice lacking Atf6. By contrast, older Atf6−/−Rho+/P23H mice developed significantly increased retinal degeneration in comparison to Atf6+/−Rho+/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.

Apoptosis, retinitis pigmentosa, and degeneration

1994 ◽  
Vol 72 (11-12) ◽  
pp. 489-498 ◽  
Author(s):  
Paul Wong
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Retinal Cell ◽  
Current Evidence ◽  
Cell Degeneration ◽  
Genetic Lesion ◽  
Common Causes ◽  
Active Cell Death

The mechanism of photoreceptor cell death in different inherited retinal degenerations is not fully understood. Mutations in a number of different genes (such as rhodopsin, the beta subunit of cGMP phosphodiesterase, and peripherin) have been identified as the primary genetic lesion in different forms of human retinitis pigmentosa, one of the most common causes of inherited blindness. In all cases the manifestation of the disorder regardless of the specific primary genetic lesion is similar, resulting in photoreceptor cell degeneration and blindness. A recent hypothesis is that the active photoreceptor cell death, which is characteristic of these genetically distinct disorders, is mediated by a common induction of apoptosis. In the present review, the current evidence for active cell death during retinal cell death in several different rodent models of retinitis pigmentosa and retinal degeneration is examined.Key words: retinal degeneration, apoptosis, retinitis pigmentosa, clusterin, DNA fragmentation.

Systems biochemistry approaches to vertebrate phototransduction: towards a molecular understanding of disease

2010 ◽  
Vol 38 (5) ◽  
pp. 1275-1280 ◽  
Author(s):  
Daniele Dell'Orco ◽  
Karl-Wilhelm Koch
Keyword(s):  
Electrical Response ◽  
Photoreceptor Cells ◽  
G Protein Coupled Receptors ◽  
Retinal Diseases ◽  
Rod Cells ◽  
Wide Range ◽  
Nucleotide Interactions ◽  
Light Stimuli ◽  
G Protein Coupled ◽  
Phototransduction Cascade

Phototransduction in vertebrates represents a paradigm of signalling pathways, in particular those mediated by G-protein-coupled receptors. The variety of protein–protein, protein–ion and protein–nucleotide interactions makes up an intricate network which is finely regulated by activating–deactivating molecules and chemical modifications. The holistic systems properties of the network allow for typical adaptation mechanisms, which ultimately result in fine adjustments of sensitivity and electrical response of the photoreceptor cells to the broad range of light stimuli. In the present article, we discuss a novel bottom-up strategy to study the phototransduction cascade in rod cells starting from the underlying biochemistry. The resulting network model can be simulated and the predicted dynamic behaviour directly compared with data from electrophysiological experiments performed on a wide range of illumination conditions. The advantage of applying procedures typical of systems theory to a well-studied signalling pathway is also discussed. Finally, the potential application to the study of the molecular basis of retinal diseases is highlighted through a practical example, namely the simulation of conditions related to Leber congenital amaurosis.

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