ArticleHuman molecular genetics2014
Hsp90 inhibition protects against inherited retinal degeneration.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 81 citations in OpenAlex.
- Cytosolic heat shock protein 90 is required for photoreceptor outer segment development and vision.The Journal of biological chemistry · 2026Article
- Restoring Sight: The Journey of AIPL1 from Discovery to Therapy.International journal of molecular sciences · 2025Review
- Hsp90Pharmaceuticals (Basel, Switzerland) · 2025Review
- Identification of novel small molecule chaperone activators for neurodegenerative disease treatment.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- P23H rhodopsin accumulation causes transient disruptions to synaptic protein levels in rod photoreceptors in a model of retinitis pigmentosa.Disease models & mechanisms · 2025Article
- TRAP1 Improves Diabetic Retinopathy by Preserving Mitochondrial Function.Clinical ophthalmology (Auckland, N.Z.) · 2025Article
- Molecular Docking, Bioinformatic Analysis, and Experimental Verification for the Effect of Naringin on ADHD: Possible Inhibition of GSK-3β and HSP90.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Updates on protein-prenylation and associated inherited retinopathies.Frontiers in ophthalmology · 2024Review
- Pathomechanisms of Inherited Retinal Degeneration and Perspectives for Neuroprotection.Cold Spring Harbor perspectives in medicine · 2023Review
- Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1.Structure (London, England : 1993) · 2023Article
- The Role of Hsp90 in Retinal Proteostasis and Disease.Biomolecules · 2022Review
- TRAP1 in Oxidative Stress and Neurodegeneration.Antioxidants (Basel, Switzerland) · 2021Review
- Pharmacological Inhibition of the VCP/Proteasome Axis Rescues Photoreceptor Degeneration in RHOBiomolecules · 2021Article
- Structural aspects of rod opsin and their implication in genetic diseases.Pflugers Archiv : European journal of physiology · 2021Review
- The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production.Molecules (Basel, Switzerland) · 2021Article
- TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells.International journal of molecular sciences · 2021Article
- HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.Thoracic cancer · 2021Article
- Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders.Frontiers in molecular biosciences · 2021Review
- Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases.Progress in retinal and eye research · 2020Review
- Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration.Investigative ophthalmology & visual science · 2020Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
The molecular chaperone Hsp90 is important for the functional maturation of many client proteins, and inhibitors are in clinical trials for multiple indications in cancer. Hsp90 inhibition activates the heat shock response and can improve viability in a cell model of the P23H misfolding mutation in rhodopsin that causes autosomal dominant retinitis pigmentosa (adRP). Here, we show that a single low dose of the Hsp90 inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in a P23H transgenic rat model. This was associated with the induction of heat shock protein expression and reduced rhodopsin aggregation. We then investigated the effect of Hsp90 inhibition on a different type of rod opsin mutant, R135L, which is hyperphosphorylated, binds arrestin and disrupts vesicular traffic. Hsp90 inhibition with 17-AAG reduced the intracellular accumulation of R135L and abolished arrestin binding in cells. Hsf-1(-/-) cells revealed that the effect of 17-AAG on P23H aggregation was dependent on HSF-1, whereas the effect on R135L was HSF-1 independent. Instead, the effect on R135L was mediated by a requirement of Hsp90 for rhodopsin kinase (GRK1) maturation and function. Importantly, Hsp90 inhibition restored R135L rod opsin localization to wild-type (WT) phenotype in vivo in rat retina. Prolonged Hsp90 inhibition with HSP990 in vivo led to a posttranslational reduction in GRK1 and phosphodiesterase (PDE6) protein levels, identifying them as Hsp90 clients. These data suggest that Hsp90 represents a potential therapeutic target for different types of rhodopsin adRP through distinct mechanisms, but also indicate that sustained Hsp90 inhibition might adversely affect visual function.
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Registered trials
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