Pharmacological Regulation of Heat Shock Response via Aptamer–Antidote Couple

Heat shock factor 1 (HSF1) orchestrates the cellular heat shock response (HSR) by binding to heat shock elements (HSEs) in the promoters of genes encoding heat shock proteins (HSPs). In a nonstressed state, HSF1 exists in a dormant complex with HSP90 and other chaperones. Upon cellular stress or upon inhibition of HSP90, HSF1 dissociates from the complex and activates the expression of HSPs to mitigate protein misfolding and aggregation. This study explores the potential of RNA aptamers selected against HSP90 to modulate HSF1 activity, with a role in Huntington's disease model characterized by protein aggregation. Selected aptamers disrupted the HSP90-HSF1 interaction, enhancing the binding of HSF1 with HSEs. This upregulated heat shock response (HSR) and reduced aggregation of Q74-huntingtin in Neuro 2a cells with improved cell survival. Designed antidote sequences could reverse the effect of the aptamers on the HSF1-HSE interaction, allowing for fine-tuning of HSR. Chronic activation of stress response pathways is deleterious for cellular fitness. Our findings suggest that coupling an antidote with an aptamer offers a novel therapeutic strategy to regulate cellular proteostasis under disease conditions.