Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa

Vats, Abhishek; Xi, Yi-Bo; Feng, Bing; Clinger, Owen D.; Leger, Anthony J. St.; Liu, Xujie; Ghosh, Archisha; Dermond, Chase D.; Lathrop, Kira L.; Tochtrop, Gregory P.; Picaud, Serge; Chen, Yuanyuan

doi:10.1172/jci.insight.153717

Cited by 9 publications

(6 citation statements)

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“…Wild type and Rho P23H/+ mice were euthanized at P15 and retina explants were isolated and cultured as previously described 107,108 . Briefly, eyeballs were enucleated and incubated in Ames solution containing 0.22 mM L-cysteine (Sigma-Aldrich) and 20 U papain (Worthington, Freehold NJ, USA) at 37 o C for 30 min.…”

Section: Efficacy Test Of Pp In Retina Explant Culturementioning

confidence: 99%

“…Proline to histidine at codon 23 (P23H) is the most common mutation in RHO protein, resulting in autosomal dominant RP in humans 63 . The heterozygous Rho P23H/+ knock-in mouse develops progressive retinal degeneration that resembles the RP phenotype in patients 64,65 . Recently, several studies suggested that boosting ERAD can protect against mouse models of RP by increased elimination of the mutant RHO P23H protein 64,[66][67][68] .…”

Section: Pp Reduces Both Pathological Tau and Rhodopsin Levels By Boo...mentioning

confidence: 99%

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SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Dion,

Tao,

Chambers

et al. 2024

Preprint

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Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

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Section: Efficacy Test Of Pp In Retina Explant Culturementioning

confidence: 99%

Section: Pp Reduces Both Pathological Tau and Rhodopsin Levels By Boo...mentioning

confidence: 99%

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Dion,

Tao,

Chambers

et al. 2024

Preprint

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“…Intriguingly, 9- cis -retinal also demonstrates strong potential to compensate for 11- cis -retinal deficiency as seen in RPE65-LCA [ 123 , 124 , 125 ] and is potentially complementary to RPE65-AAV gene therapy. More recently, non-retinoid chaperones of rhodopsin mutants have been investigated and demonstrated success in mitigating photoreceptor loss in P23H rhodopsin gene heterozygote knock-in mouse (Rho P23H/+ ), which is a model of adRP and shows progressive photoreceptor degeneration starting around P20 [ 109 , 126 ]. Thus, both chemical and pharmacological chaperones are showing promise in slowing retinal degeneration in pre-clinical studies.…”

Section: Targets and Drug Discoveries For Modulating Pathways In Phot...mentioning

confidence: 99%

Drug Discovery Strategies for Inherited Retinal Degenerations

Das

Imanishi

2022

Biology

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Inherited retinal degeneration is a group of blinding disorders afflicting more than 1 in 4000 worldwide. These disorders frequently cause the death of photoreceptor cells or retinal ganglion cells. In a subset of these disorders, photoreceptor cell death is a secondary consequence of retinal pigment epithelial cell dysfunction or degeneration. This manuscript reviews current efforts in identifying targets and developing small molecule-based therapies for these devastating neuronal degenerations, for which no cures exist. Photoreceptors and retinal ganglion cells are metabolically demanding owing to their unique structures and functional properties. Modulations of metabolic pathways, which are disrupted in most inherited retinal degenerations, serve as promising therapeutic strategies. In monogenic disorders, great insights were previously obtained regarding targets associated with the defective pathways, including phototransduction, visual cycle, and mitophagy. In addition to these target-based drug discoveries, we will discuss how phenotypic screening can be harnessed to discover beneficial molecules without prior knowledge of their mechanisms of action. Because of major anatomical and biological differences, it has frequently been challenging to model human inherited retinal degeneration conditions using small animals such as rodents. Recent advances in stem cell-based techniques are opening new avenues to obtain pure populations of human retinal ganglion cells and retinal organoids with photoreceptor cells. We will discuss concurrent ideas of utilizing stem-cell-based disease models for drug discovery and preclinical development.

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“…At present, very few non-retinoid chaperones of P23H opsin have been disclosed, most of which are still at a development stage that is far from translational or clinical applications. One of the most widely used small-molecule chaperones of P23H opsin is the non-retinoid compound named YC-001 (Figure ), a 2,5-dihydrofuran-2-one derivative discovered by a cell-based high-throughput screen, which proved able to bind non-covalently to P23H opsin and rescue its trafficking to the membrane with in vivo efficacy. , …”

Section: Introductionmentioning

confidence: 99%

“…One of the most widely used small-molecule chaperones of P23H opsin is the nonretinoid compound named YC-001 (Figure 2), a 2,5dihydrofuran-2-one derivative discovered by a cell-based high-throughput screen, which proved able to bind noncovalently to P23H opsin and rescue its trafficking to the membrane with in vivo efficacy. 21,25 Computational tools proved highly effective in the discovery of novel small-molecular chaperones of mutant opsin. 2) is a weak inhibitor of opsin regeneration providing 40% rescue of the mutant opsin, which has been discovered through the docking-based virtual screening of a drug-like library of around 24,000 small molecules.…”

Section: ■ Introductionmentioning

confidence: 99%

Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach

Picarazzi

Zuanon

Pasqualetto

et al. 2022

J. Chem. Inf. Model.

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N-terminal P23H opsin mutation accounts for most of retinitis pigmentosa (RP) cases. P23H functions and folding can be rescued by small chaperone ligands, which contributes to validate mutant opsin as a suitable target for pharmacological treatment of RP. However, the lack of structural details on P23H mutant opsin strongly impairs drug design, and new chemotypes of effective chaperones of P23H opsin are in high demand. Here, a computational-boosted workflow combining homology modeling with molecular dynamics (MD) simulations and virtual screening was used to select putative P23H opsin chaperones among different libraries through a structure-based approach. In vitro studies corroborated the reliability of the structural model generated in this work and identified a number of novel chemotypes of safe and effective chaperones able to promote P23H opsin trafficking to the outer cell membrane.

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Nonretinoid chaperones improve rhodopsin homeostasis in a mouse model of retinitis pigmentosa

Cited by 9 publications

References 68 publications

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Drug Discovery Strategies for Inherited Retinal Degenerations

Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach

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