Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Abstract Mutations in rhodopsin can cause it to misfold and lead to retinal degeneration. A distinguishing feature of these mutants in vitro is that they mislocalize and aggregate. It is unclear whether or not these features contribute to retinal degeneration observed in vivo. The effect of P23H and...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45748-4 |
| _version_ | 1797274012105048064 |
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| author | Sreelakshmi Vasudevan Subhadip Senapati Maryanne Pendergast Paul S.–H. Park |
| author_facet | Sreelakshmi Vasudevan Subhadip Senapati Maryanne Pendergast Paul S.–H. Park |
| author_sort | Sreelakshmi Vasudevan |
| collection | DOAJ |
| description | Abstract Mutations in rhodopsin can cause it to misfold and lead to retinal degeneration. A distinguishing feature of these mutants in vitro is that they mislocalize and aggregate. It is unclear whether or not these features contribute to retinal degeneration observed in vivo. The effect of P23H and G188R misfolding mutations were examined in a heterologous expression system and knockin mouse models, including a mouse model generated here expressing the G188R rhodopsin mutant. In vitro characterizations demonstrate that both mutants aggregate, with the G188R mutant exhibiting a more severe aggregation profile compared to the P23H mutant. The potential for rhodopsin mutants to aggregate in vivo was assessed by PROTEOSTAT, a dye that labels aggregated proteins. Both mutants mislocalize in photoreceptor cells and PROTEOSTAT staining was detected surrounding the nuclei of photoreceptor cells. The G188R mutant promotes a more severe retinal degeneration phenotype and greater PROTEOSTAT staining compared to that promoted by the P23H mutant. Here, we show that the level of PROTEOSTAT positive cells mirrors the progression and level of photoreceptor cell death, which suggests a potential role for rhodopsin aggregation in retinal degeneration. |
| first_indexed | 2024-03-07T14:52:18Z |
| format | Article |
| id | doaj.art-26ac64b58fb84f3593f0d411d78eb130 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:18Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-26ac64b58fb84f3593f0d411d78eb1302024-03-05T19:37:13ZengNature PortfolioNature Communications2041-17232024-02-0115112010.1038/s41467-024-45748-4Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosaSreelakshmi Vasudevan0Subhadip Senapati1Maryanne Pendergast2Paul S.–H. Park3Department of Ophthalmology and Visual Sciences, Case Western Reserve UniversityDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityAbstract Mutations in rhodopsin can cause it to misfold and lead to retinal degeneration. A distinguishing feature of these mutants in vitro is that they mislocalize and aggregate. It is unclear whether or not these features contribute to retinal degeneration observed in vivo. The effect of P23H and G188R misfolding mutations were examined in a heterologous expression system and knockin mouse models, including a mouse model generated here expressing the G188R rhodopsin mutant. In vitro characterizations demonstrate that both mutants aggregate, with the G188R mutant exhibiting a more severe aggregation profile compared to the P23H mutant. The potential for rhodopsin mutants to aggregate in vivo was assessed by PROTEOSTAT, a dye that labels aggregated proteins. Both mutants mislocalize in photoreceptor cells and PROTEOSTAT staining was detected surrounding the nuclei of photoreceptor cells. The G188R mutant promotes a more severe retinal degeneration phenotype and greater PROTEOSTAT staining compared to that promoted by the P23H mutant. Here, we show that the level of PROTEOSTAT positive cells mirrors the progression and level of photoreceptor cell death, which suggests a potential role for rhodopsin aggregation in retinal degeneration.https://doi.org/10.1038/s41467-024-45748-4 |
| spellingShingle | Sreelakshmi Vasudevan Subhadip Senapati Maryanne Pendergast Paul S.–H. Park Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa Nature Communications |
| title | Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| title_full | Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| title_fullStr | Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| title_full_unstemmed | Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| title_short | Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| title_sort | aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa |
| url | https://doi.org/10.1038/s41467-024-45748-4 |
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