Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: Neuroprotective effects of the PARP inhibitor PJ34.

Ayse Sahaboglu,François Paquet-Durand,Eberhart Zrenner,Alaa Sharif,Lili Feng,Enver Secer,Ferenc Gallyas

doi:10.1371/journal.pone.0181374

Abstract

Peripherin (peripherin/rds) is a membrane-associated protein that plays a critical role in the morphogenesis of rod and cone photoreceptor outer segments. Mutations in the corresponding PRPH2 gene cause different types of retinal dystrophies characterized by a loss of photoreceptors. Over activation of poly-ADP-ribose polymerase (PARP) was previously shown to be involved in different animal models for hereditary retinal dystrophies. This includes the rd2 mouse, which suffers from a human homologous mutation in the PRPH2 gene. In the present study, we show that increased retinal PARP activity and poly-ADP-ribosylation of proteins occurs before the peak of rd2 photoreceptor degeneration. Inhibition of PARP activity with the well-characterized PARP inhibitor PJ34 decreased the levels of poly-ADP-ribosylation and photoreceptor cell death. These results suggest a causal involvement of PARP in photoreceptor degeneration caused by peripherin mutations and highlight the possibility to use PARP inhibition for the mutation-independent treatment of hereditary retinal dystrophies.

Highlights

The photoreceptors of the retina are an exceptional type of neuron, highly specialized to their unique task of transforming photons of light into electrochemical messages
In a previous study [9], we had found that the peak of rd2 photoreceptor degeneration was at P18, as assessed by quantification of dying cells, transferase dUTP nick end labelling (TUNEL) assay in the outer nuclear layer (ONL)
Wt ONL was essentially devoid of poly-ADP-ribose polymerase (PARP) activity and signs of Poly ADP-ribose (PAR) accumulation (P16 wt PARP activity: 0.09% ± 0.05 SEM, n = 3; P16 wt PAR: 0.09% ± 0.06 SEM, n = 3) while numerous rd2 photoreceptors were positive for both (Fig 1D and 1F; P16 rd2 PARP activity: 0.98% ± 0.03 SEM, n = 3, p

Summary

Introduction

The photoreceptors of the retina are an exceptional type of neuron, highly specialized to their unique task of transforming photons of light into electrochemical messages. While rod photoreceptors are adapted to detect very low light levels, cone photoreceptors can perceive bright light with different spectral sensitivities providing for colour vision and—in the human situation—for high resolution. The signal conversion takes place in the photoreceptor outer segments (OS) where stacks of membranous disks harbour the key components of the phototransduction cascade. The edge of each OS disk is attached to the extracellular membrane by a glycoprotein called peripherin/rds [1]. Mutations in the corresponding PRPH2 gene disrupt OS architecture and are the cause of blinding hereditary retinal degeneration. Depending on the exact nature of the mutation (e.g. missense, frame-shift, premature stop) the disease

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