Pigment epithelium-derived factor hinders photoreceptor cell death by reducing intracellular calcium in the degenerating retina

Antonella Comitato,Monica Montanari,S Patricia Becerra,Valeria Marigo,Preeti Subramanian,Giandomenico Turchiano

doi:10.1038/s41419-018-0613-y

Abstract

Calcium ions play a critical role in neuronal cell death. Pigment epithelium-derived factor (PEDF) is a promising neuroprotective protein for photoreceptor cells but the mechanisms mediating its effects against retinal degeneration are still not well characterized. We addressed this question in the rd1 degenerating mouse retina that bears a mutation in the Pde6b gene encoding one subunit of the phosphodiesterase enzyme. Loss of phosphodiesterase activity in rod photoreceptor cells increases cyclic guanosine monophosphate (cGMP) levels leading to a rise in intracellular calcium. Short-term treatments with recombinant human PEDF protein decreased intracellular calcium in photoreceptors in vivo. Taking advantage of calcium pump blockers, we defined that PEDF signaling acts on PMCA calcium pumps to lower intracellular calcium. PEDF restrained cell death pathways activated by high calcium levels and engaging calpains, BAX and AIF. The neurotrophic effects were mediated by the PEDF receptor (PEDF-R), encoded by the PNPLA2 gene. Finally, peptides containing the neurotrophic domain of PEDF targeted these same cell death pathways in vivo. The findings reveal rescue from death of degenerating photoreceptor cells by a PEDF-mediated preservation of intracellular calcium homeostasis.

Highlights

Retinal degeneration is an inherited disease linked to mutations in >100 genes and this genetic heterogeneity hampers the development of a cure
In this study, we report that Pigment epithelium-derived factor (PEDF) challenges a cell death pathway in photoreceptor cells that is activated by increased intracellular Ca2+ in the degenerating rod photoreceptors bearing a loss-of-function mutation in the Pde6b gene
We showed that the 17mer and 17-mer[H105A] domains of PEDF, which bind PEDF receptor (PEDF-R), recapitulate the survival effect on degenerating photoreceptor cells like PEDF

Summary

Introduction

Retinal degeneration is an inherited disease linked to mutations in >100 genes and this genetic heterogeneity hampers the development of a cure. Pigment epithelium-derived factor (PEDF) is a protein implicated in the survival and normal function of photoreceptor cells[15]. PEDF is found in the healthy human eye and its levels are altered in eyes affected by retinal degenerative processes[16,17,18,19,20]. In human and murine eyes with retinal degeneration, PEDF levels are reduced and in animal models of retinopathies PEDF treatments protect. Comitato et al Cell Death and Disease (2018)9:560 the neuroretina, attenuate angiogenesis and neovessel invasion, and prevent loss of visual function[15,16,18,20,21]. PEDF is preferentially secreted from the apicallateral side of the retinal pigment epithelium (RPE)

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Conclusion