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

Athanasiou, D; Aguila, M; Bellingham, J; Kanuga, N; Adamson, P; Cheetham, ME; (2017) The role of the ER stress response protein PERK in rhodopsin retinitis pigmentosa. Human Molecular Genetics 10.1093/hmg/ddx370. (In press). Green open access

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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.

Type: Article
Title: The role of the ER stress response protein PERK in rhodopsin retinitis pigmentosa
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddx370
Publisher version: http://doi.org/10.1093/hmg/ddx370
Language: English
Additional information: © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Signal transduction, mutation, animals, transgenic, blindness, stress response, cell death, opsin, phosphoric monoester hydrolases, phosphorylation, photoreceptors, retinal degeneration, retinitis pigmentosa, rhodopsin, rats, retina, protein biosynthesis, catabolism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10025811
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