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Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice
- Source :
- PLoS Genetics, 15 (4)
- Publication Year :
- 2019
-
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.<br />PLoS Genetics, 15 (4)<br />ISSN:1553-7390<br />ISSN:1553-7404
- Subjects :
- Cancer Research
peripheral myelin
Fluorescent Antibody Technique
Myelin
Mice
0302 clinical medicine
Settore BIO/13 - Biologia Applicata
Homeostasis
Genetics (clinical)
Myelin Sheath
0303 health sciences
unfolded protein response
Endoplasmic Reticulum-Associated Degradation
Sciatic Nerve
Cell biology
medicine.anatomical_structure
Myelin maintenance
Peripheral nervous system
Settore MED/26 - Neurologia
proteasome activity
Research Article
Settore BIO/17 - Istologia
mouse model
Endoplasmic-reticulum-associated protein degradation
Biology
Cell Line
03 medical and health sciences
Downregulation and upregulation
Genetics
medicine
Animals
Humans
Peripheral Nerves
quality control
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
disease
proteostasis
Myelin protein zero
Endoplasmic reticulum
Gene Expression Profiling
misfolded proteins
hexosamine pathway
Unfolded protein response
neuropathy
Schwann Cells
030217 neurology & neurosurgery
Biomarkers
Demyelinating Diseases
Subjects
Details
- Language :
- English
- ISSN :
- 15537390 and 15537404
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics, 15 (4)
- Accession number :
- edsair.doi.dedup.....0c938bbad4bf4d0324fb943b63caad72