Fig. 4. Neuroprotective actions of Sig-1Rs.
Under ER stress, unfolded proteins accumulated in the ER activate ER sensor proteins PERK, ATF6 and IRE1. IRE1 and ATF6 promote upregulation of ER chaperones via activation of the ER stress response element (ERSE). Activated PERK phosphorylates eIF2α, thus leading to the inhibition of translational initiation of protein synthesis. This process is collectively called the unfolded protein response (UPR). Under prolonged ER stress ER stress, sensor proteins activate cell death pathways, including JNK and CHOP. The ER overloading response (EOR) induced by ER stress activates NF-κB, which leads to the downregulation of Bcl-2. Although protein aggregates formed in neurodegenerative disorders are often, but not always, deposited in the cytoplasm, they destruct UPR and ERAD (ER-associated degradation) systems by interacting with specific ER proteins. β-Amyloid protein and α-synuclein form protein aggregates as well as induce oxidative stress by directly activating ROS generation. ER chaperone Sig-1Rs are upregulated under ER stress to attenuate accumulation of misfolded proteins and EOR. Sig-1Rs promote cell survival in part by transcriptionally upregulating Bcl-2 expression via inhibition of the ROS/NFκB pathway. Blue and red arrows indicate cytoprotective and cell death pathways, respectively.