Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa
Rhodopsin-associated (RHO-associated) retinitis pigmentosa (RP) is a progressive retinal disease that currently has no cure. RHO protein misfolding leads to disturbed proteostasis and the death of rod photoreceptors, resulting in decreased vision. We previously identified nonretinoid chaperones of R...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153717 |
| _version_ | 1811237563574255616 |
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| author | Abhishek Vats Yibo Xi Bing Feng Owen D. Clinger Anthony J. St. Leger Xujie Liu Archisha Ghosh Chase D. Dermond Kira L. Lathrop Gregory P. Tochtrop Serge Picaud Yuanyuan Chen |
| author_facet | Abhishek Vats Yibo Xi Bing Feng Owen D. Clinger Anthony J. St. Leger Xujie Liu Archisha Ghosh Chase D. Dermond Kira L. Lathrop Gregory P. Tochtrop Serge Picaud Yuanyuan Chen |
| author_sort | Abhishek Vats |
| collection | DOAJ |
| description | Rhodopsin-associated (RHO-associated) retinitis pigmentosa (RP) is a progressive retinal disease that currently has no cure. RHO protein misfolding leads to disturbed proteostasis and the death of rod photoreceptors, resulting in decreased vision. We previously identified nonretinoid chaperones of RHO, including YC-001 and F5257-0462, by small-molecule high-throughput screening. Here, we profile the chaperone activities of these molecules toward the cell-surface level of 27 RP-causing human RHO mutants in NIH3T3 cells. Furthermore, using retinal explant culture, we show that YC-001 improves retinal proteostasis by supporting RHO homeostasis in RhoP23H/+ mouse retinae, which results in thicker outer nuclear layers (ONL), indicating delayed photoreceptor degeneration. Interestingly, YC-001 ameliorated retinal immune responses and reduced the number of microglia/macrophages in the RhoP23H/+ retinal explants. Similarly, F5257-0462 also protects photoreceptors in RhoP23H/+ retinal explants. In vivo, intravitreal injection of YC-001 or F5257-0462 microparticles in PBS shows that F5257-0462 has a higher efficacy in preserving photoreceptor function and delaying photoreceptor death in RhoP23H/+ mice. Collectively, we provide proof of principle that nonretinoid chaperones are promising drug candidates in treating RHO-associated RP. |
| first_indexed | 2024-04-12T12:25:47Z |
| format | Article |
| id | doaj.art-bde8aa97e84241c9bc43dd89c6c6a144 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:25:47Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-bde8aa97e84241c9bc43dd89c6c6a1442022-12-22T03:33:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-01710Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosaAbhishek VatsYibo XiBing FengOwen D. ClingerAnthony J. St. LegerXujie LiuArchisha GhoshChase D. DermondKira L. LathropGregory P. TochtropSerge PicaudYuanyuan ChenRhodopsin-associated (RHO-associated) retinitis pigmentosa (RP) is a progressive retinal disease that currently has no cure. RHO protein misfolding leads to disturbed proteostasis and the death of rod photoreceptors, resulting in decreased vision. We previously identified nonretinoid chaperones of RHO, including YC-001 and F5257-0462, by small-molecule high-throughput screening. Here, we profile the chaperone activities of these molecules toward the cell-surface level of 27 RP-causing human RHO mutants in NIH3T3 cells. Furthermore, using retinal explant culture, we show that YC-001 improves retinal proteostasis by supporting RHO homeostasis in RhoP23H/+ mouse retinae, which results in thicker outer nuclear layers (ONL), indicating delayed photoreceptor degeneration. Interestingly, YC-001 ameliorated retinal immune responses and reduced the number of microglia/macrophages in the RhoP23H/+ retinal explants. Similarly, F5257-0462 also protects photoreceptors in RhoP23H/+ retinal explants. In vivo, intravitreal injection of YC-001 or F5257-0462 microparticles in PBS shows that F5257-0462 has a higher efficacy in preserving photoreceptor function and delaying photoreceptor death in RhoP23H/+ mice. Collectively, we provide proof of principle that nonretinoid chaperones are promising drug candidates in treating RHO-associated RP.https://doi.org/10.1172/jci.insight.153717NeuroscienceOphthalmology |
| spellingShingle | Abhishek Vats Yibo Xi Bing Feng Owen D. Clinger Anthony J. St. Leger Xujie Liu Archisha Ghosh Chase D. Dermond Kira L. Lathrop Gregory P. Tochtrop Serge Picaud Yuanyuan Chen Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa JCI Insight Neuroscience Ophthalmology |
| title | Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| title_full | Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| title_fullStr | Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| title_full_unstemmed | Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| title_short | Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| title_sort | nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa |
| topic | Neuroscience Ophthalmology |
| url | https://doi.org/10.1172/jci.insight.153717 |
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