Abstract
Prion diseases are rare and aggressive neurodegenerative disorders caused by the accumulation of misfolded, toxic conformations of the prion protein (PrP). Therapeutic strategies directed at reducing the levels of PrP offer the best chance of delaying or halting disease progression. The challenge, though, is to define pharmacologic targets that result in reduced PrP levels. We previously reported that expression of wild type hamster PrP in flies induces progressive locomotor dysfunction and accumulation of pathogenic PrP conformations, while co-expression of human Hsp70 delayed these changes. To validate the therapeutic potential of Hsp70, we treated flies with drugs known to induce Hsp70 expression, including the Hsp90 inhibitor 17-DMAG and the glucocorticoid dexamethasone. Although the individual treatment with these compounds produced no significant benefits, their combination significantly increased the level of inducible Hsp70, decreased the level of total PrP, reduced the accumulation of pathogenic PrP conformers, and improved locomotor activity. Thus, the combined action of two pharmacological activators of Hsp70 with distinct targets results in sustained high levels of inducible Hsp70 with improved behavioral output. These findings can have important therapeutic applications for the devastating prion diseases and other related proteinopathies.
Highlights
Prion diseases encompass a diverse group of rare, aggressive, and incurable neurodegenerative conditions characterized by spongiform brain degeneration and accumulation of insoluble isoforms of the prion protein (PrP) [1]
Following up on our preliminary observations that Heat shock protein 70 (Hsp70) misexpression protects against PrP neurotoxicity, here we examined the ability of Hsp70-inducing compounds to mitigate PrP misfolding and neurotoxicity in flies
Once we found the combined regimen that induces a significant reduction on PrP levels, we set out to demonstrate that these effects are mediated by Hsp70 overexpression
Summary
Prion diseases encompass a diverse group of rare, aggressive, and incurable neurodegenerative conditions characterized by spongiform brain degeneration and accumulation of insoluble isoforms of the prion protein (PrP) [1]. 17-DMAG and Dexamethasone Rescue PrP Toxicity disease, a phenomenon observed in other protein misfolding disorders (reviewed in [11]) This proteotoxic stress response may be responsible for the typical late onset of most proteinopathies, suggesting that the protective mechanisms are overwhelmed after several years of protein accumulation, leading to neuronal dysfunction and cell loss. The individual treatments with 17-DMAG and dexamethasone produced no significant benefits, a combined regimen of 17-DMAG and dexamethasone reduced the steady-state levels of PrP, decreased the levels of pathogenic PrP conformers, and improved the locomotor performance of the flies These results indicate that pharmacological induction of Hsp activity promotes PrP degradation and prevents PrP misfolding. We have identified a new target for the therapeutic treatment of prion diseases – HSF1 – and a combination of drugs with a potent stimulatory effect on the HSF1 transcriptional target Hsp
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
