Cooling-Induced ER Stress is Good for Your Brain

Therapeutic hypothermia has been widely used to treat acute brain (Mollereau et al., 2014). It is now recognized that while severe or injury. However, this approach is not risk-free, and the underlying protectivemechanisms are poorly understood. In this issue of EbioMedicine, Rzechorzek et al. (2015) have studied the neuroprotective mechanisms induced by hypothermic preconditioning in functional cortical neurons differentiated from human pluripotent stem cells. They found that mild or moderate hypothermia induced an endoplasmic reticulum (ER) stress response and activation of the unfolded protein response (UPR), which are the cellular mechanisms that ensure correct folding of newly synthesized secreted and membrane proteins before they exit the ER (Hetz and Mollereau, 2014). This response was sufficient to protect the cells tomore severe stress – an effect known as ER hormesis – in this case, to subsequent treatmentwith oxidative and ER stressors. Inhibition of the UPR during hypothermic preconditioning abrogated the protective response. Thus, exposure of the cortical neurons to cold stress prompted a UPR-dependent adaptive response that protected against oxidative and ER stresses. How hypothermia induces the UPR and ER hormesis is unknown. One possibility is that it is simply due to aberrant folding of as yet unknown proteins at low temperatures. Alternatively, hypothermia may induce cold shock proteins such as the RNA binding motif protein 3 (RBM3), which has recently been shown to confer neuroprotection by increasing structural plasticity at the level of synapses (Peretti et al., 2015). Restoration of protein homeostasis following ER stress requires activation of the three arms of the UPR, initiated by IRE1 (inositol-requiring enzyme 1), ATF6 (activating transcription factor 6), and PERK (protein kinase RNA-like endoplasmic reticulumkinase). These pathways induce expression of chaperone proteins to facilitate protein folding, attenuate translation and trigger ER-associated degradation (ERAD) to remove aberrantly folded proteins. Interestingly, Rzechorzek et al. found that although cold stress activated the PERK pathway, induction of the downstream transcription factor CHOP did not lead to expression of Bax or to apoptosis. Instead, they found that PERK inhibitors abrogated the neuroprotection conferred by cold stress. This indicates that PERK contributes to the adaptive response induced by cold stress, possibly by stimulating an antioxidant response. These results are particularly timely given the growing interest in the function of ER stress in physiological and pathological conditions