title: 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.
authors.affiliation: Department of Ocular Biology and Therapeutics.
authors.forename: Mònica
authors.initials: M
authors.lastname: Aguilà
authors.forename: Dalila
authors.initials: D
authors.lastname: Bevilacqua
authors.forename: Caroline
authors.initials: C
authors.lastname: McCulley
authors.forename: Nele
authors.initials: N
authors.lastname: Schwarz
authors.forename: Dimitra
authors.initials: D
authors.lastname: Athanasiou
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Novoselov
authors.forename: Clemens A K
authors.initials: CA
authors.lastname: Lange
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Carlos
authors.initials: C
authors.lastname: Gias
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Coffey
authors.forename: Pere
authors.initials: P
authors.lastname: Garriga
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004596:Electroretinography; D005260:Female; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000235:genetics / Q000378:metabolism; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D041623:Tomography, Optical Coherence; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology
chemical_list: C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; D018841:HSP90 Heat-Shock Proteins; D011728:Pyridones; D011743:Pyrimidines; D012333:RNA, Messenger; D012243:Rhodopsin; D051606:G-Protein-Coupled Receptor Kinase 1