Neurons shift translational control to secure proteostatic resilience during ER stress

Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK. To study cell type-specific PERK signalling, conditional PERK-deficient (knockout; KO) neurons and astrocytes were cultured from PerkloxP/loxP mice (The Jackson Laboratory (Stock No: 023066)). Perk WT and Perk KO cells were generated by in vitro transduction with lentiviruses expressing inactive ΔCre- or active Cre-recombinase, respectively. ER stress was induced by 20-24 hours treatment with tunicamycin (TM)