Cyclic Guanosine Monophosphate: Elevation in Degenerating Photoreceptor Cells of the C3H Mouse Retina

Farber, Debora B.; Lolley, Richard N.

doi:10.1126/science.186.4162.449

Cited by 366 publications

(200 citation statements)

References 14 publications

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“…Based on other phosphodiesterase mutants, mutation of the pde6c gene would be predicted to lead an accumulation of cyclic guanosine monophosphate (cGMP). 24 We observed a dramatic accumulation of cGMP in the pde6c w59 mutant retina at 4 d.p.f., demonstrating the biochemical consequence of pde6c gene mutation (compare Figures 3c and d) and also the absence of zpr1 cone photoreceptor staining in the mutant (Figure 3c). If cone cell death was mediated through a caspase-dependent mechanism, then we would expect to see activation of caspase-3.…”

Section: Resultsmentioning

confidence: 93%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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Section: Resultsmentioning

confidence: 93%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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“…(i) A deficiency in PDE catalytic activity and subsequent accumulation of cGMP (4). The truncation produced by the nonsense codon in exon 7 would occur within the region encoding the second putative cGMP noncatalytic binding domain, eliminating the membrane binding domain and the domain presumed to be essential for enzymatic function of cyclic nucleotide PDEs (26,36).…”

Section: Methodsmentioning

confidence: 99%

“…Mice homozygous for the mutation display a complete loss of rod photoreceptor cells by postnatal day 20 (2), yet cones survive much longer, and other retinal cells remain intact (3). The detection of high levels of cGMP, followed by photoreceptor degeneration, and absence of phosphodiesterase (PDE) activity suggested a defect in the enzyme itself (4). Using immunological methods it was shown that at least one of the two large subunits of PDE is present at low levels in the homozygous mutant mouse and that a normal subunit complex, a,8y2 (5,6), which is essential for regulation of cGMP levels in the phototransduction cascade, is not formed (7).…”

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confidence: 99%

Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse.

Pittler

Baehr

1991

Proc. Natl. Acad. Sci. U.S.A.

506

273

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Retinal degeneration in the mouse mutant, rd, was previously shown to be a disorder of cyclic nucleotide metabolism involving a deficiency in the activity of the rod photoreceptor cGMP phosphodiesterase (PDE). We have characterized the normal and rd PDE (3-subunit gene, and their respective transcripts, by PCR and direct sequence analysis.We show that the gene consists of at least 22 exons ranging in size from 48 base pairs to several hundred base pairs, covering >25 kilobases. Within a 67-base-pair exon of the rd PDE (3-subunit gene, we identified a nonsense ochre mutation (a C -3 A transversion in codon 347) that truncates the normal gene product, eliminating more than one-half of the peptide chain, including the putative catalytic domain. The consequences of the truncation are consistent with the observed phenotypes in rd mice heterozygous and homozygous for the disorder. The nonsense mutation was also found in another related and in six unrelated strains displaying the rdphenotype, indicating that the rd allele arose from a single genetic event.The results strongly argue for the nonsense mutation being responsible for retinal degeneration in the rd mouse.

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“…PDE6 regulates rod cGMP levels, which in turn govern their cGMPgated cation channels (Cobbs and Pugh, 1985). The nonfunctional PDE6 therefore results in cGMP accumulation and subsequent abnormally high Ca 2ϩ levels in the rd1 photoreceptors (Farber and Lolley, 1974;Fox et al, 1999). By mostly unknown routes, this leads to an apoptotic-like rod cell death (Chang et al, 1993;Portera-Cailliau et al, 1994), followed by a mutationindependent cone death.…”

Section: Introductionmentioning

confidence: 99%

Excessive Activation of Poly(ADP-Ribose) Polymerase Contributes to Inherited Photoreceptor Degeneration in the Retinal Degeneration 1 Mouse

Paquet-Durand¹,

Silva²,

Talukdar³

et al. 2007

J. Neurosci.

130

135

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Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,Ndimethylacetamide⅐HCl] reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP.

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Cyclic Guanosine Monophosphate: Elevation in Degenerating Photoreceptor Cells of the C3H Mouse Retina

Cited by 366 publications

References 14 publications

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse.

Excessive Activation of Poly(ADP-Ribose) Polymerase Contributes to Inherited Photoreceptor Degeneration in the Retinal Degeneration 1 Mouse

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