Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice
dc.contributor.author
Volpi, Vera G.
dc.contributor.author
Ferri, Cinzia
dc.contributor.author
Fregno, Ilaria
dc.contributor.author
Del Carro, Ubaldo
dc.contributor.author
Bianchi, Francesca
dc.contributor.author
Scapin, Cristina
dc.contributor.author
Pettinato, Emanuela
dc.contributor.author
Soldà, Tatiana
dc.contributor.author
Feltri, M. Laura
dc.contributor.author
Molinari, Maurizio
dc.contributor.author
Wrabetz, Lawrence
dc.contributor.author
D’Antonio, Maurizio
dc.date.accessioned
2019-05-27T16:10:35Z
dc.date.available
2019-05-18T00:55:08Z
dc.date.available
2019-05-27T16:10:35Z
dc.date.issued
2019-04-17
dc.identifier.issn
1553-7390
dc.identifier.issn
1553-7404
dc.identifier.other
10.1371/journal.pgen.1008069
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/342835
dc.identifier.doi
10.3929/ethz-b-000342835
dc.description.abstract
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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
PLOS
dc.rights.uri
http://creativecommons.org/publicdomain/zero/1.0/
dc.title
Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice
en_US
dc.type
Journal Article
dc.rights.license
CC0 1.0 Universal
ethz.journal.title
PLoS Genetics
ethz.journal.volume
15
en_US
ethz.journal.issue
4
en_US
ethz.journal.abbreviated
PLoS Genet
ethz.pages.start
e1008069
en_US
ethz.size
30 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
San Francisco, CA
ethz.publication.status
published
en_US
ethz.date.deposited
2019-05-18T00:55:11Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2019-05-27T16:10:56Z
ethz.rosetta.lastUpdated
2024-02-02T08:09:14Z
ethz.rosetta.versionExported
true
ethz.COinS
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Journal Article [130185]