Ablation of the UPR-Mediator CHOP Restores Motor Function and Reduces Demyelination in Charcot-Marie-Tooth 1B Mice

Maria Pennuto, Elisa Tinelli, MariaChiara Malaguti, Ubaldo Del Carro, Maurizio D'Antonio, David Ron, Angelo Quattrini, M. Laura Feltri, Lawrence Wrabetz

Research output: Contribution to journalArticlepeer-review

Abstract

Deletion of serine 63 from P0 glycoprotein (P0S63del) causes Charcot-Marie-Tooth 1B neuropathy in humans, and P0S63del produces a similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that P0S63del is misfolded and Schwann cells mount a consequential canonical unfolded protein response (UPR), including expression of the transcription factor CHOP, previously associated with apoptosis in ER-stressed cells. UPR activation and CHOP expression respond dynamically to P0S63del levels and are reversible but are associated with only limited apoptosis of Schwann cells. Nonetheless, Chop ablation in S63del mice completely rescues their motor deficit and reduces active demyelination 2-fold. This indicates that signaling through the CHOP arm of the UPR provokes demyelination in inherited neuropathy. S63del mice also provide an opportunity to explore how cells can dysfunction yet survive in prolonged ER stress-important for neurodegeneration related to misfolded proteins.

Original languageEnglish
Pages (from-to)393-405
Number of pages13
JournalNeuron
Volume57
Issue number3
DOIs
Publication statusPublished - Feb 7 2008

Keywords

  • HUMDISEASE
  • MOLNEURO
  • PROTEINS

ASJC Scopus subject areas

  • Neuroscience(all)

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