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

Cell Death & Disease
Antonella ComitatoValeria Marigo

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 preser...Continue Reading

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Citations

Apr 5, 2020·Neural Regeneration Research·Meltem KutluerValeria Marigo
Oct 4, 2020·International Journal of Molecular Sciences·Francisco J Valiente-SorianoManuel Vidal-Sanz
Jan 31, 2019·International Journal of Molecular Sciences·Thierry Léveillard, Laurence Klipfel
Aug 28, 2020·International Journal of Molecular Sciences·Abdullah Al-AniMark Ungrin
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Sep 3, 2020·MethodsX·Jeanee BullockS Patricia Becerra
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Apr 18, 2021·Pflügers Archiv : European journal of physiology·Soumyaparna DasFrançois Paquet-Durand
Jun 3, 2021·International Journal of Molecular Sciences·Ivan T RebustiniS Patricia Becerra
Jul 3, 2021·International Journal of Molecular Sciences·Li HuangValeria Marigo
Jul 30, 2020·Experimental Eye Research·Shivani DixitS Patricia Becerra

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