PUBLICATION

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Authors
Viringipurampeer, I.A., Shan, X., Gregory-Evans, K., Zhang, J.P., Mohammadi, Z., and Gregory-Evans, C.Y.
ID
ZDB-PUB-140317-24
Date
2014
Source
Cell death and differentiation   21(11): 1320-9 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Death/genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 6/genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism
  • Gene Knockdown Techniques
  • Receptor-Interacting Protein Serine-Threonine Kinases/deficiency*
  • Receptor-Interacting Protein Serine-Threonine Kinases/genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
  • Retinal Cone Photoreceptor Cells/metabolism
  • Retinal Cone Photoreceptor Cells/pathology*
  • Retinal Degeneration/genetics*
  • Retinal Degeneration/metabolism
  • Retinal Degeneration/pathology
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed
24413151 Full text @ Cell Death Differ.
Abstract

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 pde6cw59 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 pde6cw59 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 pde6cw59 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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