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Dual therapeutic approaches to rhodopsin retinitis pigmentosa through Hsp90 inhibition

aguila, monica, bevilacqua, dalila and cheetham, michael (3276) Dual therapeutic approaches to rhodopsin retinitis pigmentosa through Hsp90 inhibition. Human Molecular Genetics, 23 (8). pp. 2164-2175. ISSN 0964-69061460-2083


Retinitis pigmentosa (RP) is characterized by the progressive degeneration of retinal photoreceptor neurons. Mutations in rhodopsin are the most common cause of autosomal dominant Retinitis pigmentosa (adRP). Therapies targeting multiple classes of mutations would be of a great value for retinal dystrophies. It has been previously shown that pharmacological interventions can improve the folding and traffic, or reduce protein aggregation of the class II rod opsin misfolding mutant, P23H. We investigated the capacity of these interventions to modulate the class III rod opsin mutant, R135L, which binds arrestin and disrupts vesicular traffic. R135L acted as a dominant negative, and recruited wild-type rod opsin to intracellular vesicles. Treatment with retinoids or kosmotropes did not improve the vesicular disruption caused by R135L. By contrast, Hsp90 inhibition reduced the intracellular accumulation of R135L and abolished arrestin binding. This effect was mediated by a requirement for Hsp90 in kinase (GRK1) function, which is upstream of arrestin binding. Furthermore, prolonged high dose Hsp90 inhibition reduced photoreceptor GRK1 and PDE without affecting photoreceptor viability. Interestingly, a single low dose inhibition of Hsp90 protected against photoreceptor degeneration caused by P23H rod opsin, without affecting these components but correlated with an activation of HSF1 and heat shock protein induction. These data suggest that Hsp90 could be used as a potential therapeutic target for different types of rhodopsin adRP, but that inhibition might also affect the visual function through the requirement for Hsp90 in the biogenesis of phototransduction machinery components.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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