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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. Author summary Charcot-Marie-Tooth neuropathies are a large family of peripheral nerve disorders, showing extensive clinical and genetic heterogeneity. Although strong advances have been made in the identification of genes and mutations involved, effective therapies are still lacking. Intracellular retention of abnormal proteins has been recently suggested as one of the pathogenetic events that might underlie several conformational neuropathies. To limit the toxic effects of accumulated mutant proteins, cells have developed efficient protein quality control systems aimed at optimizing both protein folding and degradation. Here we show that ER-associated degradation limits Schwann cells stress and myelin defects caused by the accumulation of a mutant myelin protein into the ER. In addition, we also describe for the first time the importance of Schwann cells ERAD in preserving myelin integrity in adult nerves, showing that genetic ERAD impairment leads to a late onset, motor-predominant, peripheral neuropathy in vivo. Effort in the design of strategies that potentiate ERAD and ER quality controls is therefore highly desirable.
2019
