The role of the ER stress-response protein PERK in rhodopsin retinitis pigmentosa.

Dimitra Athanasiou,Naheed Kanuga,James Bellingham,Michael E Cheetham,Peter Adamson,Monica Aguila

doi:10.1093/hmg/ddx370

Abstract

Mutations in rhodopsin, the light-sensitive protein of rod cells, are the most common cause of dominant retinitis pigmentosa (RP), a type of inherited blindness caused by the dysfunction and death of photoreceptor cells. The P23H mutation, the most frequent single cause of RP in the USA, causes rhodopsin misfolding and induction of the unfolded protein response (UPR), an adaptive ER stress response and signalling network that aims to enhance the folding and degradation of misfolded proteins to restore proteostasis. Prolonged UPR activation, and in particular the PERK branch, can reduce protein synthesis and initiate cell death through induction of pro-apoptotic pathways. Here, we investigated the effect of pharmacological PERK inhibition on retinal disease process in the P23H-1 transgenic rat model of retinal degeneration. PERK inhibition with GSK2606414A led to an inhibition of eIF2α phosphorylation, which correlated with reduced ERG function and decreased photoreceptor survival at both high and low doses of PERK inhibitor. Additionally, PERK inhibition increased the incidence of inclusion formation in cultured cells overexpressing P23H rod opsin, and increased rhodopsin aggregation in the P23H-1 rat retina, suggesting enhanced P23H misfolding and aggregation. In contrast, treatment of P23H-1 rats with an inhibitor of eIF2α phosphatase, salubrinal, led to improved photoreceptor survival. Collectively, these data suggest the activation of PERK is part of a protective response to mutant rhodopsin that ultimately limits photoreceptor cell death.

Highlights

Retinitis pigmentosa (RP) is a group of inherited diseases that cause the progressive dysfunction and degeneration of rod and cone photoreceptor cells in the retina leading to blindness
GSK2606414A is a potent and selective inhibitor of protein kinase RNA-like ER kinase (PERK), it is functionally active in cells, and inhibits PERK with a selectivity of >385 fold over other eukaryotic initiation factor 2a (eIF2a) kinases and a panel of 294 kinases, and has excellent central nervous system (CNS) penetration following oral dosing [14,30]
We tested the ability of GSK2606414A (PERKi) to modify photoreceptor degeneration in the P23H-1 transgenic rat

Summary

Introduction

Retinitis pigmentosa (RP) is a group of inherited diseases that cause the progressive dysfunction and degeneration of rod and cone photoreceptor cells in the retina leading to blindness. The light sensing protein of rod cells, are the single most common cause of autosomal dominant RP, which primarily affect rod cells followed by the secondary loss of cone cells [1]. The majority of mutations are class II mutations and cause protein misfolding, such as P23H, the most common mutation in the USA [2]. The misfolded protein is retained in the endoplasmic reticulum (ER) and degraded by the proteasome. If mutant rhodopsin is not efficiently degraded it can aggregate and form intracellular inclusions, similar to those found in many other neurodegenerative diseases [3,4]. P23H rhodopsin expression induces the unfolded protein response (UPR) [5], a signalling network that senses imbalances between protein synthesis, quality control and degradation in the ER

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