Schwann cells produce a considerable amount of lipids and proteins to form myelin in the peripheral nervous system (PNS). For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and mice. Misfolded P0S63del accumulates in the endoplasmic reticulum (ER) of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/ PerkSCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo . We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with Calcineurin/NFATc4 pro-myelinating path...