The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. If the stress is prolonged, or the adaptive response fails, apoptotic cell death ensues. Many studies have focused on how this failure initiates apoptosis, as ER stress-induced apoptosis is implicated in the pathophysiology of several neurodegenerative and cardiovascular diseases. Cell Stress Discoveries Ltd. has been founded with the goal of developing therapeutic candidate molecules that can modify the molecular switch from the adaptive phase to apoptosis and vice versa.
ER stress conditions have been observed in numerous diseases including Alzheimer disease, Creutzfeldt–Jakob disease, Huntington disease as well as cardiovascular diseases, indicating that ER stressinduced apoptosis is an important factor in pathophysiological conditions. To be able to treat or halt the progress of such conditions, a firm understanding of the mechanisms mediating ER stress-induced apoptosis is essential. Research so far has identified many candidates involved in orchestrating the switch from the protective UPR signalling to pro-apoptotic signalling. Some of these genes, such as P58IPK, GADD34 and TRB3, are involved in switching off the PERKmediated pathway. Blocking this protective pathway can be a central element of the switch from adaptation to suicide.
Many proteins with negative-feedback functions including CHOP and ASK1 are activated during the UPR. Both overexpression and knockout experiments have confirmed the pro-apoptotic role of these proteins in ER stress. Both molecules can target the BCL2 family and are able to set the death machinery in motion. Furthermore, activation of ASK1 might be regulated by stress-sensitive adaptor proteins such as JAB1, offering another possible mechanism to switch from an adaptive response to cell suicide. It is also worth mentioning that, dissimilar to other stress responses, the mediators of ER stress are well defined and are specific to ER stress; therefore, they may be useful targets for therapy. Inhibition of the IRE1–TRAF2 interaction by small chemicals or by antagonistic IRE1-interacting adaptor proteins is also a strategy that CSD Ltd. is investigating.