Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration

2008 ◽  
Vol 38 (3) ◽  
pp. 253-269 ◽  
Author(s):  
Javier Sancho-Pelluz ◽  
Blanca Arango-Gonzalez ◽  
Stefan Kustermann ◽  
Francisco Javier Romero ◽  
Theo van Veen ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Cell Death Mechanisms ◽  
Inherited Retinal Degeneration

scholarly journals MutT Homolog-1 Attenuates Oxidative DNA Damage and Delays Photoreceptor Cell Death in Inherited Retinal Degeneration

2012 ◽  
Vol 181 (4) ◽  
pp. 1378-1386 ◽  
Author(s):  
Yusuke Murakami ◽  
Yasuhiro Ikeda ◽  
Noriko Yoshida ◽  
Shoji Notomi ◽  
Toshio Hisatomi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Retinal Degeneration ◽  
Oxidative Dna Damage ◽  
Photoreceptor Cell ◽  
Inherited Retinal Degeneration

scholarly journals RNA Biological Characteristics at the Peak of Cell Death in Different Hereditary Retinal Degeneration Mutants

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunling Wei ◽  
Yan Li ◽  
Xiaoxiao Feng ◽  
Zhulin Hu ◽  
François Paquet-Durand ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factors ◽  
Network Analysis ◽  
Retinal Degeneration ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Photoreceptor Cell ◽  
Predictive Biomarkers ◽  
Retinal Tissue ◽  
Inherited Retinal Degeneration

Purpose: The present work investigated changes in the gene expression, molecular mechanisms, and pathogenesis of inherited retinal degeneration (RD) in three different disease models, to identify predictive biomarkers for their varied phenotypes and to provide a better scientific basis for their diagnosis, treatment, and prevention.Methods: Differentially expressed genes (DEGs) between retinal tissue from RD mouse models obtained during the photoreceptor cell death peak period (Pde6brd1 at post-natal (PN) day 13, Pde6brd10 at PN23, Prphrd2 at PN29) and retinal tissue from C3H wild-type mice were identified using Illumina high-throughput RNA-sequencing. Co-expression gene modules were identified using a combination of GO and KEGG enrichment analyses and gene co-expression network analysis. CircRNA-miRNA-mRNA network interactions were studied by genome-wide circRNA screening.Results:Pde6brd1, Pde6brd10, and Prphrd2 mice had 1,926, 3,096, and 375 DEGs, respectively. Genes related to ion channels, stress, inflammatory processes, tumor necrosis factor (TNF) production, and microglial cell activation were up-regulated, while genes related to endoplasmic reticulum regulation, metabolism, and homeostasis were down-regulated. Differential expression of transcription factors and non-coding RNAs generally implicated in other human diseases was detected (e.g., glaucoma, diabetic retinopathy, and inherited retinal degeneration). CircRNA-miRNA-mRNA network analysis indicated that these factors may be involved in photoreceptor cell death. Moreover, excessive cGMP accumulation causes photoreceptor cell death, and cGMP-related genes were generally affected by different pathogenic gene mutations.Conclusion: We screened genes and pathways related to photoreceptor cell death. Additionally, up-stream regulatory factors, such as transcription factors and non-coding RNA and their interaction networks were analyzed. Furthermore, RNAs involved in RD were functionally annotated. Overall, this study lays a foundation for future studies on photoreceptor cell death mechanisms.

scholarly journals Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Soumyaparna Das ◽  
Valerie Popp ◽  
Michael Power ◽  
Kathrin Groeneveld ◽  
Jie Yan ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Strong Increase ◽  
Channel Blockers ◽  
Photoreceptor Degeneration ◽  
Therapy Development ◽  
Hypertensive Drug ◽  
Future Therapy

AbstractHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

scholarly journals Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0239108
Author(s):  
Ryo Terauchi ◽  
Hideo Kohno ◽  
Sumiko Watanabe ◽  
Saburo Saito ◽  
Akira Watanabe ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Fluorescent Protein ◽  
Outer Nuclear Layer ◽  
Inhibitory Effect ◽  
Subretinal Space ◽  
Photoreceptor Degeneration ◽  
Retinal Inflammation ◽  
Green Fluorescent

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

Inhibition of LOX-1 prevents inflammation and photoreceptor cell death in retinal degeneration

2020 ◽  
Vol 80 ◽  
pp. 106190
Author(s):  
Xinran Gao ◽  
Ruilin Zhu ◽  
Jiantong Du ◽  
Wenbo Zhang ◽  
Wenna Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell

scholarly journals AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death

2020 ◽  
Vol 19 ◽  
pp. 144-156 ◽  
Author(s):  
Marianthi Karali ◽  
Irene Guadagnino ◽  
Elena Marrocco ◽  
Rossella De Cegli ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Microglia Activation

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 Early mitochondrial stress and metabolic imbalance lead to photoreceptor cell death in retinal degeneration

2021 ◽  
Author(s):  
Ke Jiang ◽  
Anupam K Mondal ◽  
Yogita Adlakha ◽  
Jessica Gumerson ◽  
Angel M Aponte ◽  
...  
Keyword(s):  
Cell Death ◽  
Calcium Signaling ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Ex Vivo ◽  
Transcriptome Profiling ◽  
Central Carbon Metabolism ◽  
Pentose Phosphate ◽  
Mitochondrial Stress ◽  
And Function

Neurodegenerative diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset and severity. To deduce the mechanism leading to retinal degeneration, we adopted a temporal multi-omics approach and examined molecular and cellular events before the onset of photoreceptor cell death in the widely-used Pde6brd1/rd1 (rd1) mouse model. Transcriptome profiling of neonatal and developing rods revealed early downregulation of genes associated with anabolic pathways and energy metabolism. Quantitative proteomics of rd1 retina showed early changes in calcium signaling and oxidative phosphorylation, with specific partial bypass of complex I electron transfer, which precede the onset of cell death. Concurrently, we detected alterations in central carbon metabolism, including dysregulation of components associated with glycolysis, pentose phosphate and purine biosynthesis. Ex vivo assays of oxygen consumption and transmission electron microscopy validated early and progressive mitochondrial stress and abnormalities in mitochondrial structure and function of rd1 rods. These data uncover mitochondrial over-activation and related metabolic alterations as early determinants of pathology and implicate dysregulation of calcium signaling as the initiator of higher mitochondrial stress, which then transitions to mitochondrial damage and photoreceptor cell death in retinal degeneration. Our studies support the one hit model arguing against the cumulative damage hypothesis but suggest that cell death in neurodegenerative disease is initiated by specific rather than a random event.

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