Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1 B mice

Deletion of serine 63 from PO glycoprotein (POS63del) causes Charcot-Marie-Tooth 1 B neuropathy in humans, and POS63del produces a similar demyelinating neuropathy in transgenic mice. POS63del is retained in the endoplasmic reticulum and fails to be incorporated into myelin. Here we report that POS63clel is mis-folded 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 POS63del 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.