Aguilà, M; Bevilacqua, D; McCulley, C; Schwarz, N; Athanasiou, D; Kanuga, N; Novoselov, SS; ... Cheetham, ME; + view all Aguilà, M; Bevilacqua, D; McCulley, C; Schwarz, N; Athanasiou, D; Kanuga, N; Novoselov, SS; Lange, CA; Ali, RR; Bainbridge, JW; Gias, C; Coffey, PJ; Garriga, P; Cheetham, ME; - view fewer (2014) Hsp90 inhibition protects against inherited retinal degeneration. Hum Mol Genet , 23 (8) pp. 2164-2175. 10.1093/hmg/ddt613.

Preview

PDF Hum._Mol._Genet.-2014-Aguilà-2164-75.pdf Download (1MB)

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, R135 L, which is hyperphosphorylated, binds arrestin and disrupts vesicular traffic. Hsp90 inhibition with 17-AAG reduced the intracellular accumulation of R135 L and abolished arrestin binding in cells. Hsf1(-/-) cells revealed that the effect of 17-AAG on P23H aggregation was dependent on HSF-1, whereas the effect on R135 L was HSF-1 independent. Instead, the effect on R135 L was mediated by a requirement of Hsp90 for rhodopsin kinase (GRK1) maturation and function. Importantly, Hsp90 inhibition restored R135 L rod opsin localization to WT phenotype in vivo in rat retina. Prolonged Hsp90 inhibition with HSP990 in vivo led to a post-translational 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.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item