Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice.

Authors:
Cinzia Ferri
Cinzia Ferri
IRCCS San Raffaele Scientific Institute
Italy
Ubaldo Del Carro
Ubaldo Del Carro
University Vita-Salute San Raffaele
Italy
Francesca Bianchi
Francesca Bianchi
University of Turin
Italy
Cristina Scapin
Cristina Scapin
Floating Hospital for Children at Tufts Medical Center
Emanuela Pettinato
Emanuela Pettinato
IRCCS San Raffaele Scientific Institute
Italy
Tatiana Solda
Tatiana Solda
Institute for Research in Biomedicine

PLoS Genet 2019 Apr 17;15(4):e1008069. Epub 2019 Apr 17.

Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffused genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P0-S63del), result in misfolding and accumulation of P0 in the endoplasmic reticulum (ER), with activation of the unfolded protein response (UPR). In addition, we observed that S63del mouse nerves display the upregulation of many ER-associated degradation (ERAD) genes, suggesting a possible involvement of this pathway in the clearance of the mutant P0. In ERAD in fact, misfolded proteins are dislocated from the ER and targeted for proteasomal degradation. Taking advantage of inducible cells that express the ER retained P0, here we show that the P0-S63del glycoprotein is degraded via ERAD. Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affects adult myelin maintenance in normal nerves, without compromising their development, pinpointing ERAD as a previously unrecognized player in preserving Schwann cells homeostasis in adulthood. Finally, we provide evidence that treatment of S63del peripheral nerve cultures with N-Acetyl-D-Glucosamine (GlcNAc), known to enhance protein quality control pathways in C.elegans, ameliorates S63del nerve myelination ex vivo. Overall, our study suggests that potentiating adaptive ER quality control pathways might represent an appealing strategy to treat both conformational and age-related PNS disorders.

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http://dx.plos.org/10.1371/journal.pgen.1008069
Publisher Site
http://dx.doi.org/10.1371/journal.pgen.1008069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488099PMC
April 2019
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