A rat model for retinitis pigmentosa with rapid retinal degeneration enables drug evaluation in vivo
Open Access
- 4 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Biological Procedures Online
- Vol. 23 (1), 1-11
- https://doi.org/10.1186/s12575-021-00150-y
Abstract
Background: Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine. Results: A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death. Conclusions: In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.Keywords
Funding Information
- Japan Society for the Promotion of Science (15K10883)
This publication has 22 references indexed in Scilit:
- Generation of a Transgenic Rabbit Model of Retinal DegenerationInvestigative Ophthalmology & Visual Science, 2009
- Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancementNeurobiology of Disease, 2008
- Programmed Cell Death in Retinal Degeneration: Targeting Apoptosis in Photoreceptors as Potential Therapy for Retinal DegenerationCell Cycle, 2007
- Identification of an Outer Segment Targeting Signal in the Cooh Terminus of Rhodopsin Using Transgenic Xenopus laevisThe Journal of cell biology, 2000
- Crystal Structure of Rhodopsin: A G Protein-Coupled ReceptorScience, 2000
- Genetically engineered large animal model for studying cone photoreceptor survival and degeneration in retinitis pigmentosaNature Biotechnology, 1997
- Transgenic mice carrying the dominant rhodopsin mutation P347S: Evidence for defective vectorial transport of rhodopsin to the outer segmentsProceedings of the National Academy of Sciences of the United States of America, 1996
- Mechanisms of Rhodopsin Inactivation in Vivo as Revealed by a COOH-Terminal Truncation MutantScience, 1995
- Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosaNeuron, 1992
- Mutations within the Rhodopsin Gene in Patients with Autosomal Dominant Retinitis PigmentosaThe New England Journal of Medicine, 1990