Calcineurin Activity Is Increased in Charcot-Marie-Tooth 1B Demyelinating Neuropathy

Schwann cells produce a considerable amount of lipids and proteins to form myelin in the 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 neuropathy in humans and mice. Misfolded P0S63del accumulates in the 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/Perk(SCKO)) 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 pathway. Using mouse genetics including females and males in our experimental setting, we show that PERK and calcineurin interact in P0S63del nerves and that calcineurin activity and NFATc4 nuclear localization are increased in S63del Schwann cells, without altering EGR2/KROX20 expression. Moreover, genetic manipulation of the calcineurin subunits appears to be either protective or toxic in S63del in a context-dependent manner, suggesting that Schwann cells are highly sensitive to alterations of calcineurin activity.