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

by Vera G. Volpi, Cinzia Ferri, Ilaria Fregno, Ubaldo Del Carro, Francesca Bianchi, Cristina Scapin, Emanuela Pettinato, Tatiana Solda, M. Laura Feltri, Maurizio Molinari, Lawrence Wrabetz, Maurizio D ’Antonio 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 diffus ed 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 mou se 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 inducib le 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 UPRin vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affec...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research