Phosphorylation of eIF2a promotes schwann cell differentiation and myelination in CMT1B mice with activated UPR

Cristina Scapin, Cinzia Ferri, Emanuela Pettinato, Francesca Bianchi, Ubaldo Del Carro, M. Laura Feltri, Randal J. Kaufman, Lawrence Wrabetz, Maurizio D'Antonio

Research output: Contribution to journalArticlepeer-review

Abstract

Myelin Protein Zero (MPZ/P0) is the most abundant glycoprotein of peripheral nerve myelin. P0 is synthesized by myelinating Schwann cells, processed in the endoplasmic reticulum (ER) and delivered to myelin via the secretory pathway. The mutant P0S63del (deletion of serine 63 in the extracellular domain of P0), that causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and a similar demyelinating neuropathy in transgenic mice, is instead retained the ER where it activates an unfolded protein response. Under ER-stress conditions, protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylates eukaryotic initiation factor 2a (eIF2a) to attenuate global translation, thus reducing the misfolded protein overload in the ER. Genetic and pharmacological inactivation of Gadd34 (damage-inducible protein 34), a subunit of the PP1 phosphatase complex that promotes the dephosphorylation of eIF2a, prolonged eIF2a phosphorylation and improved motor, neurophysiological, and morphologic deficits in S63del mice. However, PERK ablation in S63del Schwann cells ameliorated, rather than worsened, S63del neuropathy despite reduced levels of phosphorylated eIF2a. These contradictory findings prompted us to genetically explore the role of eIF2a phosphorylation in P0S63del-CMT1B neuropathy through the generation of mice in which eIF2a cannot be phosphorylated specifically in Schwann cells. Morphologic and electrophysiological analysis of male and female S63del mice showed a worsening of the neuropathy in the absence of eIF2a phosphorylation. However, we did not detect significant changes in ER stress levels, but rather a dramatic increase of the MEK/ERK/c-Jun pathway accompanied by a reduction in expression of myelin genes and a delay in Schwann cell differentiation. Our results support the hypothesis that eIF2a phosphorylation is protective in CMT1B and unveil a possible cross talk between eIF2a and the MEK/ERK pathway in neuropathic nerves.

Original languageEnglish
Pages (from-to)8174-8187
Number of pages14
JournalJournal of Neuroscience
Volume40
Issue number42
DOIs
Publication statusPublished - Oct 14 2020

Keywords

  • EIF2a
  • ER stress
  • Myelin
  • Neuropathy
  • Schwann cell
  • UPR

ASJC Scopus subject areas

  • Neuroscience(all)

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