The role of Perk in myelination and demyelinating CMT1B neuropathy
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Myelin is a multilamellar structure that insulates the axons, to provide fast conduction of electrical impulses and protection. Schwann cells (SCs) are the myelinating glia of the peripheral nervous system (PNS) and produce an enormous amount of proteins and lipids to form myelin. As a consequence, Schwann cells are considered professional factory cells, where quality control of myelin proteins is highly regulated. For example, deletion of serine 63 from P0 (P0S63del) produces a misfolded protein that accumulates in the endoplasmic reticulum (ER) and elicits the unfolded protein response (UPR) in myelin forming Schwann cells. The toxic P0S63del causes Charcot-Marie-Tooth type 1B (CMT1B) demyelinating neuropathy both in humans and mice and the UPR is the main pathomechanism. In fact, PERK, ATF6 and IRE1 transduction pathways of the UPR are active in S63del nerves. In particular, PERK kinase attenuates global translation and reduces ER stress through phosphorylation of the translation initiation factor eIF2α. GADD34 is part of the holophosphatase that dephosphorylates eIF2α, reactivating protein translation as a negative feedback on PERK activation. We previously showed that impairment of GADD34 (S63del//Gadd34Δc/Δc) enhances eIF2αP and rescues S63del neuropathy by limiting global translation. Here we show that Perk ablation, specifically in S63del Schwann cells (S63del// Perk SCKO ), decreased the level of eIF2αP, thus disrupting the translational homeostasis in neuropathic nerves. Nonetheless, cell-specific depletion of Perk in Schwann cells, but not in neurons, paradoxically improved the demyelinating phenotype of P0S63del mice. We investigated the hypothesis that other UPR arms might compensate for the loss of Perk. However, the UPR markers are similarly upregulated in S63del and S63del// Perk SCKO , with no overt activation in absence of Perk. Moreover, P0 misfolded protein remained extensively accumulated in the Schwann cell ER indicating that ER stress is persistent in S63del// Perk SCKO Schwann cells and UPR mediators do not compensate for Perk loss of function. Collectively, these data suggest that PERK has an eIF2α-independent effect. In particular, we hypothesized that PERK may interfere with signals outside of the UPR. In fact, we provide preliminary evidence that PERK may regulate the Calcineurin (CaN)/NFATc4 pro-myelinating pathway and alter myelination by Schwann cells in CMT1B neuropathy.