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Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia

Sarkar, Hajrah; Lahne, Manuela; Nair, Neelima; Moosajee, Mariya; (2023) Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia. Antioxidants , 12 (9) , Article 1694. 10.3390/antiox12091694. Green open access

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Abstract

Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy, affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, with no approved therapy. CHM is caused by mutations in the CHM gene, which encodes the ubiquitously expressed Rab escort protein 1 (REP1). REP1 is involved in prenylation, a post-translational modification of Rab proteins, and plays an essential role in intracellular trafficking. In this study, we examined oxidative and endoplasmic reticulum (ER) stress pathways in chmru848 zebrafish and CHMY42X patient fibroblasts, and screened a number of neuroprotectants for their ability to reduce stress. The expression of the oxidative stress markers txn, cat and sod3a, and the ER stress markers bip, atf4 and atf6, were dysregulated in chmru848 fish. The expression of SOD2 was also reduced in CHMY42X fibroblasts, along with reduced BIP and increased CHOP expression. The lack of REP1 is associated with defects in vesicular trafficking, photoreceptor outer segment phagocytosis and melanosome transport, leading to increased levels of stress within the retina and RPE. Drugs targeting oxidative and ER stress pathways represent novel therapeutic avenues.

Type: Article
Title: Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/antiox12091694
Publisher version: https://doi.org/10.3390/antiox12091694
Language: English
Additional information: © 2023 by the Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: choroideremia; oxidative stress; ER stress; neuroprotectants; zebrafish; patient fibroblasts
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/10176260
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