Abstract
Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor.
Highlights
Rhodopsin is formed of rod opsin protein and the chromophore 11-cis-retinal
Arimoclomol is an heatshock response (HSR) potentiating compound; we initially investigated the effect of arimoclomol on HSR activation in SK-N-SH cells expressing wild-type or P23H rod opsin tagged with GFP (WT-GFP and P23H-GFP, respectively)
There appeared to be a small decrease in the amount of higher molecular weight species of P23H-GFP rod opsin in treated cells compared with untreated cells (Figure 1c), potentially corresponding to higher-order complexes of rod opsin
Summary
Rhodopsin is formed of rod opsin protein and the chromophore 11-cis-retinal. The most common point mutation in. ATF6 (activating transcription factor 6) traffics to the Golgi, where it is cleaved, and the N-terminal fragment enters the nucleus, where it upregulates molecular chaperones and quality-control components. Hsp[90] inhibitors, such as geldanamycin and its analogues, bind the ATP-binding pocket of Hsp[90] and block its ATPase cycle, releasing HSF1, which can activate heat-shock protein expression.[17,18] Inhibition of Hsp[90] can reduce P23H rhodopsin inclusion formation, insolubility and reduce P23H rod opsin-associated cell death.[19] Recently, Hsp[90] inhibition was shown to reduce P23H rhodopsin-mediated photoreceptor cell death in vivo but can potentially affect normal visual function, suggesting that other mechanisms to induce the stress response might be desirable.[20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
