Early manifestations and differential gene expression associated with photoreceptor degeneration in Prominin-1-deficient retina

Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations including those in the Prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for Endothelin-2 (Edn2) being markedly up-regulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases.

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Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

10.1101/2020.12.07.405308 ◽

2020 ◽

Author(s):

Yuka Kobayashi ◽

Shizuka Watanabe ◽

Manabu Shirai ◽

Chiemi Yamashiro ◽

Tadahiko Ogata ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Cell Activation ◽

Photoreceptor Cell ◽

Macular Dystrophy ◽

Endothelin Receptor Antagonists ◽

Endothelin Receptor ◽

Receptor Antagonists ◽

Causative Gene ◽

High Throughput Analysis

AbstractRetinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.728791 ◽

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.

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

Cell Death and Disease ◽

10.1038/s41419-021-04482-1 ◽

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.

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

PLoS ONE ◽

10.1371/journal.pone.0239108 ◽

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.

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Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration

Molecular Neurobiology ◽

10.1007/s12035-008-8045-9 ◽

2008 ◽

Vol 38 (3) ◽

pp. 253-269 ◽

Cited By ~ 168

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

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Dental pulp stem cells therapy overcome photoreceptor cell death and protects the retina in a rat model of sodium iodate-induced retinal degeneration

Journal of Photochemistry and Photobiology B Biology ◽

10.1016/j.jphotobiol.2019.111561 ◽

2019 ◽

Vol 198 ◽

pp. 111561 ◽

Cited By ~ 3

Author(s):

Hiba Amer Alsaeedi ◽

Avin Ee-Hwan Koh ◽

Chenshen Lam ◽

Munirah Binti Abd Rashid ◽

Mohd Hairul Nizam Harun ◽

...

Keyword(s):

Stem Cells ◽

Cell Death ◽

Retinal Degeneration ◽

Rat Model ◽

Dental Pulp ◽

Photoreceptor Cell ◽

Dental Pulp Stem Cells ◽

Sodium Iodate ◽

Stem Cells Therapy

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

International Immunopharmacology ◽

10.1016/j.intimp.2020.106190 ◽

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

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

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2019.11.005 ◽

2020 ◽

Vol 19 ◽

pp. 144-156 ◽

Cited By ~ 5

Author(s):

Marianthi Karali ◽

Irene Guadagnino ◽

Elena Marrocco ◽

Rossella De Cegli ◽

Annamaria Carissimo ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Microglia Activation

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Apoptosis, retinitis pigmentosa, and degeneration

Biochemistry and Cell Biology ◽

10.1139/o94-066 ◽

1994 ◽

Vol 72 (11-12) ◽

pp. 489-498 ◽

Cited By ~ 48

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.

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