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

AbstractThe second messengers, cGMP and Ca2+, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca2+)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca2+-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca2+ permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca2+-dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications.

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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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Redefining the role of Ca2+-permeable channels in hereditary photoreceptor degeneration using the D- and L-cis enantiomers of diltiazem

10.1101/2020.12.04.411827 ◽

2020 ◽

Author(s):

Soumyaparna Das ◽

Valerie Popp ◽

Michael Power ◽

Kathrin Groeneveld ◽

Christian Melle ◽

...

Keyword(s):

Cell Death ◽

Photoreceptor Cell ◽

Strong Increase ◽

Channel Blockers ◽

Photoreceptor Degeneration ◽

Therapy Development ◽

Hypertensive Drug ◽

Future Therapy ◽

Reduced Activity

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 highly effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pores of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced 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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Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽

10.3390/biom10010100 ◽

2020 ◽

Vol 10 (1) ◽

pp. 100 ◽

Cited By ~ 5

Author(s):

Gur P. Kaushal ◽

Kiran Chandrashekar ◽

Luis A. Juncos ◽

Sudhir V. Shah

Keyword(s):

Cell Death ◽

Renal Injury ◽

Mammalian Target Of Rapamycin ◽

Kidney Injury ◽

Therapeutic Approaches ◽

Regulated Necrosis ◽

Atg Genes ◽

Cellular Components ◽

The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis

Cell Calcium ◽

10.1016/j.ceca.2006.08.016 ◽

2006 ◽

Vol 40 (5-6) ◽

pp. 553-560 ◽

Cited By ~ 394

Author(s):

György Hajnóczky ◽

György Csordás ◽

Sudipto Das ◽

Cecilia Garcia-Perez ◽

Masao Saotome ◽

...

Keyword(s):

Cell Death ◽

Calcium Signalling ◽

Mitochondrial Calcium

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Dysfunction of Heterotrimeric Kinesin-2 in Rod Photoreceptor Cells and the Role of Opsin Mislocalization in Rapid Cell Death

Molecular Biology of the Cell ◽

10.1091/mbc.e10-08-0715 ◽

2010 ◽

Vol 21 (23) ◽

pp. 4076-4088 ◽

Cited By ~ 31

Author(s):

Vanda S. Lopes ◽

David Jimeno ◽

Kornnika Khanobdee ◽

Xiaodan Song ◽

Bryan Chen ◽

...

Keyword(s):

Cell Death ◽

Outer Segment ◽

Photoreceptor Cell ◽

Photoreceptor Cells ◽

Cell Loss ◽

Rod Photoreceptor ◽

Retinal Degenerations ◽

Cell Counts ◽

And Function

Due to extensive elaboration of the photoreceptor cilium to form the outer segment, axonemal transport (IFT) in photoreceptors is extraordinarily busy, and retinal degeneration is a component of many ciliopathies. Functional loss of heterotrimeric kinesin-2, a major anterograde IFT motor, causes mislocalized opsin, followed by rapid cell death. Here, we have analyzed the nature of protein mislocalization and the requirements for the death of kinesin-2-mutant rod photoreceptors. Quantitative immuno EM showed that opsin accumulates initially within the inner segment, and then in the plasma membrane. The light-activated movement of arrestin to the outer segment is also impaired, but this defect likely results secondarily from binding to mislocalized opsin. Unlike some other retinal degenerations, neither opsin–arrestin complexes nor photoactivation were necessary for cell loss. In contrast, reduced rod opsin expression provided enhanced rod and cone photoreceptor survival and function, as measured by photoreceptor cell counts, apoptosis assays, and ERG analysis. The cell death incurred by loss of kinesin-2 function was almost completely negated by Rho−/−. Our results indicate that mislocalization of opsin is a major cause of photoreceptor cell death from kinesin-2 dysfunction and demonstrate the importance of accumulating mislocalized protein per se, rather than specific signaling properties of opsin, stemming from photoactivation or arrestin binding.

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Loss of Ift74 Leads to Slow Photoreceptor Degeneration and Ciliogenesis Defects in Zebrafish

International Journal of Molecular Sciences ◽

10.3390/ijms22179329 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9329

Author(s):

Panpan Zhu ◽

Jingjin Xu ◽

Yadong Wang ◽

Chengtian Zhao

Keyword(s):

Cell Death ◽

Photoreceptor Cell ◽

Genetic Disorders ◽

Intraflagellar Transport ◽

Photoreceptor Degeneration ◽

Transport Efficiency ◽

Zebrafish Development ◽

Multiple Organs ◽

Wide Range ◽

Different Types

Cilia are microtubule-based structures projecting from the cell surface that perform diverse biological functions. Ciliary defects can cause a wide range of genetic disorders known collectively as ciliopathies. Intraflagellar transport (IFT) proteins are essential for the assembly and maintenance of cilia by transporting proteins along the axoneme. Here, we report a lack of Ift74, a core IFT-B protein, leading to ciliogenesis defects in multiple organs during early zebrafish development. Unlike rapid photoreceptor cell death in other ift-b mutants, the photoreceptors of ift74 mutants exhibited a slow degeneration process. Further experiments demonstrated that the connecting cilia of ift74 mutants were initially formed but failed to maintain, which resulted in slow opsin transport efficiency and eventually led to photoreceptor cell death. We also showed that the large amount of maternal ift74 transcripts deposited in zebrafish eggs account for the main reason of slow photoreceptor degeneration in the mutants. Together, our data suggested Ift74 is critical for ciliogenesis and that Ift proteins play variable roles in different types of cilia during early zebrafish development. To our knowledge, this is the first study to show ift-b mutant that displays slow photoreceptor degeneration in zebrafish.

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The role of caspases in photoreceptor cell death of the retinoschisin-deficient mouse

Cytogenetic and Genome Research ◽

10.1159/000094799 ◽

2006 ◽

Vol 115 (1) ◽

pp. 35-44 ◽

Cited By ~ 9

Author(s):

A. Gehrig ◽

A. Janssen ◽

F. Horling ◽

C. Grimm ◽

B.H.F. Weber

Keyword(s):

Cell Death ◽

Photoreceptor Cell ◽

Deficient Mouse

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Analysis of Fox genes in Schmidtea mediterranea reveals new families and a conserved role of Smed-foxO in controlling cell death

Scientific Reports ◽

10.1038/s41598-020-80627-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eudald Pascual-Carreras ◽

Carlos Herrera-Úbeda ◽

Maria Rosselló ◽

Pablo Coronel-Córdoba ◽

Jordi Garcia-Fernàndez ◽

...

Keyword(s):

Cell Death ◽

Phylogenetic Reconstruction ◽

Single Copy ◽

Schmidtea Mediterranea ◽

Functional Studies ◽

New Family ◽

Gene Diversification ◽

Fox Genes ◽

Key Aspects

AbstractThe forkhead box (Fox) genes encode transcription factors that control several key aspects of development. Present in the ancestor of all eukaryotes, Fox genes underwent several duplications followed by loss and diversification events that gave rise to the current 25 families. However, few Fox members have been identified from the Lophotrochozoa clade, and specifically from planarians, which are a unique model for understanding development, due to the striking plasticity of the adult. The aim of this study was to identify and perform evolutionary and functional studies of the Fox genes of lophotrochozoan species and, specifically, of the planarian Schmidtea mediterranea. Generating a pipeline for identifying Forkhead domains and using phylogenetics allowed us the phylogenetic reconstruction of Fox genes. We corrected the annotation for misannotated genes and uncovered a new family, the QD, present in all metazoans. According to the new phylogeny, the 27 Fox genes found in Schmidtea mediterranea were classified into 12 families. In Platyhelminthes, family losses were accompanied by extensive gene diversification and the appearance of specific families, the A(P) and N(P). Among the newly identified planarian Fox genes, we found a single copy of foxO, which shows an evolutionary conserved role in controlling cell death.

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