Hsp90 inhibition protects against inherited retinal degeneration

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.

Inherent Instability of the Retinitis Pigmentosa P23H Mutant Opsin

“…Gene delivery of the chaperone proteins preserved retinal structure and function in P23H TG rats (21,22). Interestingly, a single low dose of the heat-shock protein 90 (Hsp90) inhibitor HSP990 enhanced visual function and delayed photoreceptor degeneration in P23H TG rats, most likely by promoting degradation of the mutant protein (23). More recently, a P23H knock-in mouse model was developed to more faithfully recapitulate the genotype and phenotype of adRP patients.…”

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…The observed symptoms include night blindness, photopsia, blurred vision, and visual impairment, which are likely associated with retinal dysfunction (20,21). Two independent reports of rodent models suggest that HSP90 plays a critical role in retinal function and that sustained HSP90 inhibition might adversely affect visual function (34,49). Therefore, ocular effects may be minimized by reducing retinal exposure.…”

AIPL1: A specialized chaperone for the phototransduction effector

“…Several LCA-associated mutations within the TPR-domain of AIPL1 impacted its interaction with HSP90 [59]. Furthermore, pharmacological inhibition of HSP90 reduced the stability of PDE6 in mouse retina [60]. Altogether, these studies strongly implicate the HSP90 chaperone machinery in folding/assembly of PDE6, and AIPL1 as an obligate specialized co-chaperone, which is recruited to the chaperone-client complex via its FKBP and TPR-domains.…”