1. Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa
- Author
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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, McGowan Institute for Regenerative Medicine [Pittsburgh, PA, USA] (MGIRM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Pennsylvania Commonwealth System of Higher Education (PCSHE), Case Western Reserve University [Cleveland], Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Marazova, Katia
- Subjects
Pharmacology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Rhodopsin ,[SDV]Life Sciences [q-bio] ,G protein–coupled receptors ,General Medicine ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,[SDV] Life Sciences [q-bio] ,Ophthalmology ,Disease Models, Animal ,Mice ,Retinal Rod Photoreceptor Cells ,NIH 3T3 Cells ,Animals ,Homeostasis ,Retinitis Pigmentosa ,Neuroscience ,Protein misfolding ,Molecular Chaperones - Abstract
International audience; 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.
- Published
- 2021
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