Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse

• Published in: The Journal of neuroscience 2016-11, Vol.36 (44), p.11350-11361
• Main Authors: Sidoli, Mariapaola, Musner, Nicolò, Silvestri, Nicholas, Ungaro, Daniela, D'Antonio, Maurizio, Cavener, Douglas R, Feltri, M Laura, Wrabetz, Lawrence
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; eIF-2 Kinase - metabolism; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin P0 Protein - genetics; Myelin P0 Protein - metabolism; Myelin Sheath - metabolism; Myelin Sheath - pathology; Schwann Cells - metabolism; Schwann Cells - pathology; Unfolded Protein Response
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1637-16.2016

In factory cells, the accumulation of misfolded protein provokes the unfolded protein response (UPR). For example, deletion of serine 63 (S63del) in myelin protein zero (P0) induces P0 accumulation in the endoplasmic reticulum (ER) of Schwann cells and a persistent UPR associated with Charcot-Marie-Tooth 1B (CMT1B) demyelinating peripheral neuropathy in human and mouse. PERK (protein kinase RNA-like ER kinase) is the ER stress sensor that attenuates global translation by phosphorylating eIF2α. Inhibition of the eIF2α holophosphatase GADD34:PP1, increases the phosphorylation of eIF2α in Schwann cells and largely rescues S63del neuropathy. Nonetheless, reducing phosphorylation of eIF2α, by Perk haploinsufficiency, also ameliorates the myelin defects of S63del nerves. This contradictory finding prompted us to investigate whether the beneficial effect of Perk deficiency on myelination could derive from neurons. To test this hypothesis, we generated and compared Schwann cell- and neuron-specific ablation of Perk in S63del nerves. Our data suggest that the detrimental effect of Perk in CMT1B derives primarily from Schwann cells. Furthermore, we show that Perk loss of function in Schwann cells restores myelination without diminishing accumulation of P0 or markers of ER stress, suggesting that Perk may modulate myelination through a pathway independent of the UPR. In many endoplasmic reticulum (ER) stress-related disorders, activation of the unfolded protein sensor protein kinase RNA-like ER kinase (PERK) kinase is beneficial. Nonetheless, in Charcot-Marie-Tooth 1B neuropathy mice, we show that activation of PERK in Schwann cells, but not in neurons, is detrimental for myelination. PERK may interfere with myelination, independent of its role in ER stress.