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Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model
Open accessPublished version of a preprint
Abstract
Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of Txnip in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP’s structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.
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Metadata
- Authors
- Xue, Y., Zhou, Y., & Cepko, C. L.
- Affiliations
- Harvard University (US)
- ShanghaiTech University (CN)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cepko, Constance L
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2024-05-10
- Volume
- 12
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC11087050
- OpenAlex
- W4386769899
- Cited by
- 4
- References
- 2
- Citations by year
- 2025: 3 · 2024: 1
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Eye Institute (K99EY030951)
- Howard Hughes Medical Institute
- Lingang Laboratory (Start up fund)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- retinitis pigmentosa, TXNIP, retinal pigment epithelium, alpha-arrestin, HSP90AB1, gene deletion, AAV gene therapy, structure-function relationship
- MeSH terms
- Alleles, Animals, Carrier Proteins, Cell Survival, Disease Models, Animal, Retinitis Pigmentosa, Thioredoxins, Gene Deletion, Retinal Cone Photoreceptor Cells, Mutation, Missense, Mice, Retinal Pigment Epithelium
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