The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

Das, Soumyaparna; Chen, Yiyi; Yan, Jie; Christensen, Gustav; Belhadj, Soumaya; Tolone, Arianna; Paquet-Durand, François

doi:10.1007/s00424-021-02556-9

Cited by 38 publications

(22 citation statements)

References 117 publications

(152 reference statements)

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“…Activation of ER stress causes a cascade effect which suppresses anti-apoptotic markers BCL2 and BCL-XL and promotes cell death through mechanisms such as apoptosis and autophagy ( Figure 3 ). In achromatopsia mutations, excessive intracellular calcium (Ca 2+ ) has been observed in cones, with Ca 2+ toxicity being linked to cell death regulation [ 107 , 108 , 109 , 110 ]. This unregulated Ca 2+ influx leads to ER stress indicated by the increase in ER stress markers such as 1,4,5-trisphosphate (IP 3 ), eukaryotic initiation factor 2α (eIF2α), and CCAAT/-enhancer-binding protein homologous protein (CHOP) [ 28 , 29 , 110 ].…”

Section: Cellular Stressmentioning

confidence: 99%

Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options

Brunet

Harvey

Carvalho

2022

IJMS

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Inherited retinal diseases (IRDs) are a leading cause of blindness. To date, 260 disease-causing genes have been identified, but there is currently a lack of available and effective treatment options. Cone photoreceptors are responsible for daylight vision but are highly susceptible to disease progression, the loss of cone-mediated vision having the highest impact on the quality of life of IRD patients. Cone degeneration can occur either directly via mutations in cone-specific genes (primary cone death), or indirectly via the primary degeneration of rods followed by subsequent degeneration of cones (secondary cone death). How cones degenerate as a result of pathological mutations remains unclear, hindering the development of effective therapies for IRDs. This review aims to highlight similarities and differences between primary and secondary cone cell death in inherited retinal diseases in order to better define cone death mechanisms and further identify potential treatment options.

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Section: Cellular Stressmentioning

confidence: 99%

Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options

Brunet

Harvey

Carvalho

2022

IJMS

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“…While Ca 2+ is extruded from the outer segment by the Na + /Ca 2+ -K + (NCKX) exchanger, Na + is pumped out of the inner segment by the adenosine-5′-triphosphate (ATP) -driven Na + /K + exchanger (NKX). This continuous flow of Na + ions forms the circulating dark current ( Figure 1 ) [ 21 ].…”

Section: Photoreceptor Physiology and Phototransductionmentioning

confidence: 99%

“…Unfortunately, these attempts generally failed to yield tangible success [ 102 , 103 , 104 ], which may indicate that Ca 2+ influx is, in fact, not as relevant for photoreceptor cell death as previously thought [ 96 ]. The lack of therapeutic effect of Ca 2+ channel blockers also suggests that the main drivers of cGMP-dependent photoreceptor cell death are mainly independent of Ca 2+ [ 21 ].…”

Section: Cgmp-dependent Cell Death In Rdmentioning

confidence: 99%

Programmed Non-Apoptotic Cell Death in Hereditary Retinal Degeneration: Crosstalk between cGMP-Dependent Pathways and PARthanatos?

Yan

Chen

Zhu

et al. 2021

IJMS

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Programmed cell death (PCD) is a highly regulated process that results in the orderly destruction of a cell. Many different forms of PCD may be distinguished, including apoptosis, PARthanatos, and cGMP-dependent cell death. Misregulation of PCD mechanisms may be the underlying cause of neurodegenerative diseases of the retina, including hereditary retinal degeneration (RD). RD relates to a group of diseases that affect photoreceptors and that are triggered by gene mutations that are often well known nowadays. Nevertheless, the cellular mechanisms of PCD triggered by disease-causing mutations are still poorly understood, and RD is mostly still untreatable. While investigations into the neurodegenerative mechanisms of RD have focused on apoptosis in the past two decades, recent evidence suggests a predominance of non-apoptotic processes as causative mechanisms. Research into these mechanisms carries the hope that the knowledge created can eventually be used to design targeted treatments to prevent photoreceptor loss. Hence, in this review, we summarize studies on PCD in RD, including on apoptosis, PARthanatos, and cGMP-dependent cell death. Then, we focus on a possible interplay between these mechanisms, covering cGMP-signaling targets, overactivation of poly(ADP-ribose)polymerase (PARP), energy depletion, Ca2+-permeable channels, and Ca2+-dependent proteases. Finally, an outlook is given into how specific features of cGMP-signaling and PARthanatos may be targeted by therapeutic interventions.

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“…Loss of function PDE6 mutation resulted in decreased PDE6α/β activity and a high cytoplasmic cGMP concentration (Tsang et al, 1996). Photoreceptor cell physiology relies on the regulation and interplay of the second messenger signaling molecule cGMP and Ca 2+ levels (Vighi et al, 2018;Das et al, 2021). Classic opsin signaling involves cGMP-gated ion channels; high intracellular cGMP concentrations perpetually open cGMP-gated ion channels, leading to increased Ca 2+ influx and, ultimately, photoreceptor degeneration (Dean et al, 2002).…”

Section: Wnt/β-catenin Signaling Protects Photoreceptors From Degradationmentioning

confidence: 99%

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

Wei

Feng

et al. 2021

Front. Genet.

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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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The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

Cited by 38 publications

References 117 publications

Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options

Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options

Programmed Non-Apoptotic Cell Death in Hereditary Retinal Degeneration: Crosstalk between cGMP-Dependent Pathways and PARthanatos?

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

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