@article{8883bef3357e4b958ec2012e934dcbf7,
title = "Calcineurin activity is increased in Charcot-Marie-Tooth 1B demyelinating neuropathy",
abstract = "Schwann cells produce a considerable amount of lipids and proteins to form myelin in the PNS. For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B neuropathy in humans and mice. Misfolded P0S63del accumulates in the ER of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/PerkSCKO) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo. We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with calcineurin/NFATc4 pro-myelinating pathway. Using mouse genetics including females and males in our experimental setting, we show that PERK and calcineurin interact in P0S63del nerves and that calcineurin activity and NFATc4 nuclear localization are increased in S63del Schwann cells, without altering EGR2/KROX20 expression. Moreover, genetic manipulation of the calcineurin subunits appears to be either protective or toxic in S63del in a context-dependent manner, suggesting that Schwann cells are highly sensitive to alterations of calcineurin activity.",
author = "Mariapaola Sidoli and Reed, {Chelsey B.} and Cristina Scapin and Pablo Paez and Cavener, {Douglas R.} and Kaufman, {Randal J.} and Maurizio D{\textquoteright}Antonio and Feltri, {M. Laura} and Lawrence Wrabetz",
note = "Funding Information: This work was supported by National Institutes of Health Grants R01 and R56NS096104 to L.W. and Grant NS045630 to M.L.F.; Telethon Italy GGP071100 to L.W.; GGP08821 to M.L.F.; GGP14147 to M.D.; European Community FP7/2007-1013 under Grant Agreement HEALTH-F2-2008-201535 to L.W. and M.L.F.; Charcot-Marie-Tooth Association to L.W.; and Italian Ministry of Health GR-2011-02346791 to M.D. R.J.K. was supported in part by National Institutes of Health Grants CA198103, DK113171, and AG062190. M.S. was supported by NMSS Fellowship FG-1807-31636. We thank Ed Hurley for the processing of sciatic nerves for semithin and electron microscopy, Virginia Lee (University of Pennsylvania) for anti-MBP antibodies, and Dies Mejer (University of Edinburgh) for anti-EGR2 antibodies. The authors declare no competing financial interests. Funding Information: This work was supported by National Institutes of Health Grants R01 and R56NS096104 to L.W. and Grant NS045630 to M.L.F.; Telethon Italy GGP071100 to L.W.; GGP08821 to M.L.F.; GGP14147 to M.D.; European Community FP7/2007-1013 under Grant Agreement HEALTH-F2-2008-201535 to L.W. and M.L.F.; Charcot-Marie-Tooth Association to L.W.; and Italian Ministry of Health GR-2011-02346791 to M.D. R.J.K. was supported in part by National Institutes of Health Grants CA198103, DK113171, and AG062190. M.S. was supported by NMSS Fellowship FG-1807-31636. We thank Ed Hurley for the processing of sciatic nerves for semithin and electron microscopy, Virginia Lee (University of Pennsylvania) for anti-MBP antibodies, and Dies Mejer (University of Edinburgh) for anti-EGR2 antibodies. Publisher Copyright: Copyright {\textcopyright} 2021 the authors",
year = "2021",
month = may,
day = "19",
doi = "10.1523/JNEUROSCI.2384-20.2021",
language = "English (US)",
volume = "41",
pages = "4536--4548",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "20",
}