Guarascio, Rosellina;
Ziaka, Kalliopi;
Hau, Kwan-Leong;
Piccolo, Davide;
Nieuwenhuis, Sara Eliza;
Bakoulina, Adriana;
Asfahani, Rowan;
... Cheetham, Michael E; + view all
(2025)
Preventing light-induced toxicity in a new mouse model of sector retinitis pigmentosa caused by Rhodopsin M39R variant.
Cell Death Discovery
, 11
, Article 477. 10.1038/s41420-025-02769-2.
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Preventing light-induced toxicity in a new mouse model of sector retinitis pigmentosa caused by Rhodopsin M39R variant.pdf - Published Version Download (3MB) | Preview |
Abstract
Retinitis Pigmentosa (RP) is an inherited retinal dystrophy characterised by the progressive loss of rod photoreceptors. Sector RP is a form of RP where degeneration originates in the inferior retina, mainly influenced by light exposure. Over 200 RHO variants are pathogenic and associated with autosomal dominant RP. RHOM39R is one of the most common RHO variants linked to sector RP in the UK. A knock-in (KI) mouse model expressing RhoM39R was generated and characterised to investigate the mechanisms of degeneration associated with this variant and explore novel therapeutic strategies for rhodopsin sector RP. Under cyclic ambient light, RhoM39R/+ KI mice exhibited impaired retinal function by ERG, with some defects in OS ultrastructure, but retained normal outer nuclear layer (ONL) thickness. Repeated exposure to bright light led to photoreceptor loss. In contrast, RhoM39R/M39R KI mice in cyclic ambient light displayed severe retinal dysfunction, ONL thinning, and grossly abnormal OS ultrastructure. In homozygous mice, a single bright light exposure significantly reduced ONL thickness within 48 h. The rescue of these models was achieved through reduced light exposure and pharmacological intervention. Rearing in dim red light (red cage condition) restored ERG responses in RhoM39R/+ KI mice and improved ONL thickness in RhoM39R/M39R KI mice. Transcriptomic analysis in RhoM39R/M39R KI mice revealed upregulation of Sphingosine 1-P Receptor (S1pr) transcripts. Treatment with the S1PR agonist Fingolimod (FTY720) before bright light exposure significantly reduced degeneration, demonstrating a protective effect in both heterozygous and homozygous models and suggesting potential as a therapeutic approach for sector RP patients.
| Type: | Article |
|---|---|
| Title: | Preventing light-induced toxicity in a new mouse model of sector retinitis pigmentosa caused by Rhodopsin M39R variant |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41420-025-02769-2 |
| Publisher version: | https://doi.org/10.1038/s41420-025-02769-2 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| 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/10216288 |
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