Cellular stress responses in protein misfolding diseases

Abstract

Many human diseases, particularly neurodegenerative diseases, are associated with protein misfolding. Cellular protein quality control includes all processes that ensure proper protein folding and thus prevent the toxic consequences of protein misfolding. The heat shock response (HSR) and the unfolded protein response (UPR) are major stress response pathways within protein quality control that antagonize protein misfolding in the cytosol and the endoplasmic reticulum, respectively. Huntington's disease is an inherited neurodegenerative disease caused by the misfolding of an abnormally expanded polyglutamine (polyQ) region in the protein huntingtin (Htt), polyQHtt. Using Huntington's disease as a paradigm, I review here the central role of both the HSR and the UPR in defining the toxicity associated with polyQHtt in Huntington's disease. These findings may begin to unravel a previously unappreciated cooperation between different stress response pathways in cells expressing misfolded proteins and consequently in neurodegenerative diseases.

Keywords: cellular protein quality control; heat shock response; polyQ expansion diseases; protein misfolding; stress response pathways; unfolded protein response.

Figure 1.. Key signaling and transcriptional events.

Events in (A) the HSR and (B) the UPR. ER: Endoplasmic reticulum; ERAD: Endoplasmic reticulum-associated protein degradation; HSE: Heat shock element; HSR:Heat shock response; UPR:Unfolded protein response; UPRE:Unfolded protein response elements; UPS: Ubiquitin proteasome system.

Figure 2.. The heat shock response and the unfolded protein response act together in exacerbating polyQ toxicity in Huntington's disease.

The ‘?’ indicates a possible albeit hitherto mostly unexplored direct connection between the HSR and the UPR. ERAD: Endoplasmic reticulum-associated protein degradation; HSR: Heat shock response; UPR: Unfolded protein response.