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 A rat model for retinitis pigmentosa with rapid retinal degeneration enables drug evaluation in vivo

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Chisato Inoue ◽  
Tamaki Takeuchi ◽  
Akira Shiota ◽  
Mineo Kondo ◽  
Yuji Nshizawa
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Rat Model ◽  
Photoreceptor Cell ◽  
Photoreceptor Cells ◽  
Therapeutic Agents ◽  
Transgenic Rat ◽  
Cell Degeneration ◽  
Rat Strain

Abstract Background Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine. Results A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death. Conclusions In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.

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.

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 Suppression of Light-Induced Retinal Degeneration by Quercetin via the AP-1 Pathway in Rats

Antioxidants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 79 ◽  
Author(s):  
Yasurou Koyama ◽  
Sachiko Kaidzu ◽  
Yong-Chul Kim ◽  
Yotaro Matsuoka ◽  
Tomoe Ishihara ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Light Exposure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Intraperitoneal Administration ◽  
Binding Activity ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Fluorescent Light ◽  
Cell Degeneration

We examined the cytoprotective effect of quercetin via activator protein (AP-1) and the heat shock protein 70 (Hsp70) pathway against light-induced retinal degeneration in rats. Quercetin was administered intraperitoneally to Sprague-Dawley rats for seven days before light exposure to intense white fluorescent light (3000 lux) for 24 h. Light-induced retinal damage was determined by the number of rows of photoreceptor cell nuclei, the microstructures of the rod outer segments and retinal pigment epithelium, and terminal deoxynucleotidyl transferase (TdT)-mediated 2'-Deoxyuridine-5'-triphosphate (dUTP) nick end labeling. To elucidate the cytoprotective mechanism of quercetin, expression levels were measured in the rat retinas of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative stress; Hsp70; and transcription factor AP-1 transcription activity. Pretreatment with quercetin inhibited light-induced photoreceptor cellular apoptosis and subsequent retinal degeneration in rats. 8-OHdG and Hsp70 protein expressions were up-regulated markedly by light exposure and suppressed by quercetin pretreatment. The results of an electrophoretic mobility shift assay showed that AP-1-binding activity was activated by light exposure, and binding of c-Fos and c-Jun, but not JunB, mediated the binding activity. Intraperitoneal administration of quercetin decreases photooxidative damage in the retina and mediates cytoprotection against light-induced photoreceptor cell degeneration in rats. Suppression of the heterodimeric combination of c-Jun and c-Fos proteins at the AP-1 binding site is highly involved in quercetin-mediated cytoprotection.

scholarly journals NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration

2016 ◽  
Vol 25 (8) ◽  
pp. 1501-1516 ◽  
Author(s):  
Ishaq A. Viringipurampeer ◽  
Andrew L. Metcalfe ◽  
Abu E. Bashar ◽  
Olena Sivak ◽  
Anat Yanai ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Nlrp3 Inflammasome ◽  
Photoreceptor Cell ◽  
Inflammasome Activation ◽  
Cone Photoreceptor ◽  
Nlrp3 Inflammasome Activation

scholarly journals Automated cone photoreceptor cell identification in confocal adaptive optics scanning laser ophthalmoscope images based on object detection

2021 ◽  
pp. 2250001
Author(s):  
Yiwei Chen ◽  
Yi He ◽  
Jing Wang ◽  
Wanyue Li ◽  
Lina Xing ◽  
...  
Keyword(s):  
Object Detection ◽  
Adaptive Optics ◽  
Photoreceptor Cell ◽  
Ground Truth ◽  
Photoreceptor Cells ◽  
Detection Algorithm ◽  
Scanning Laser Ophthalmoscope ◽  
Scanning Laser ◽  
Cone Photoreceptor ◽  
Cell Identification

Cone photoreceptor cell identification is important for the early diagnosis of retinopathy. In this study, an object detection algorithm is used for cone cell identification in confocal adaptive optics scanning laser ophthalmoscope (AOSLO) images. An effectiveness evaluation of identification using the proposed method reveals precision, recall, and [Formula: see text]-score of 95.8%, 96.5%, and 96.1%, respectively, considering manual identification as the ground truth. Various object detection and identification results from images with different cone photoreceptor cell distributions further demonstrate the performance of the proposed method. Overall, the proposed method can accurately identify cone photoreceptor cells on confocal adaptive optics scanning laser ophthalmoscope images, being comparable to manual identification.

scholarly journals Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity

2017 ◽  
Vol 114 (39) ◽  
pp. E8264-E8273 ◽  
Author(s):  
Yoshihiro Omori ◽  
Shun Kubo ◽  
Tetsuo Kon ◽  
Mayu Furuhashi ◽  
Hirotaka Narita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Photoreceptor Cell ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Photoreceptor Cells ◽  
Rod Photoreceptor ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Null Mutant Mice

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

Müller cell changes precede photoreceptor cell degeneration in the age-related retinal degeneration of the Fischer 344 rat

1995 ◽  
Vol 698 (1-2) ◽  
pp. 1-14 ◽  
Author(s):  
David A. DiLoreto ◽  
Mark R. Martzen ◽  
Constancia del Cerro ◽  
Paul D. Coleman ◽  
Manuel del Cerro
Keyword(s):  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Müller Cell ◽  
Cell Degeneration ◽  
Fischer 344 ◽  
Age Related ◽  
Fischer 344 Rat ◽  
Muller Cell ◽  
Cell Changes

scholarly journals Suppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in Drosophila

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009172
Author(s):  
Jaiwei Xu ◽  
Haifang Zhao ◽  
Tao Wang
Keyword(s):  
Retinal Degeneration ◽  
Therapeutic Strategy ◽  
Photoreceptor Cells ◽  
Cell Degeneration ◽  
E3 Ligases ◽  
Genome Wide ◽  
A Genome ◽  
Coa Reductase ◽  
Mutant Forms ◽  
Erad Pathway

Mutations in the gene rhodopsin are one of the major causes of autosomal dominant retinitis pigmentosa (adRP). Mutant forms of Rhodopsin frequently accumulate in the endoplasmic reticulum (ER), cause ER stress, and trigger photoreceptor cell degeneration. Here, we performed a genome-wide screen to identify suppressors of retinal degeneration in a Drosophila model of adRP, carrying a point mutation in the major rhodopsin, Rh1 (Rh1G69D). We identified two novel E3 ubiquitin ligases SORDD1 and SORDD2 that effectively suppressed Rh1G69D-induced photoreceptor dysfunction and retinal degeneration. SORDD1/2 promoted the ubiquitination and degradation of Rh1G69D through VCP (valosin containing protein) and independent of processes reliant on the HRD1 (HMG-CoA reductase degradation protein 1)/HRD3 complex. We further demonstrate that SORDD1/2 and HRD1 function in parallel and in a redundant fashion to maintain rhodopsin homeostasis and integrity of photoreceptor cells. These findings identify a new ER-associated protein degradation (ERAD) pathway and suggest that facilitating SORDD1/2 function may be a therapeutic strategy to treat adRP.

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