on May 17, 2019
Maurizio Molinari (IRB), Lawrence Wrabetz (Hunter James Kelly Research Institute, University at Buffalo, Buffalo, New York, USA) and Maurizio D’Antonio (San Raffaele Scientific Institute, Milan Italy) research groups have recently published an article in PLOS Genetics entitled “Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination”. The work is the results of a fruitful collaboration between the three research groups that combined here their expertise.
Myelin protein zero (P0) is the major structural protein produced by myelinating Schwann cells. P0 is synthesized in the endoplasmic reticulum (ER) and is transported to the plasma membrane where its main function is to stabilize the myelin sheaths in the peripheral nervous system via homophilic association of the extracellular P0 domains. More than 100 mutations in the P0 gene (MPZ) have been identified as the cause of Charcot-Marie Tooth 1B (CMT1B) neuropathy, a pathology characterized by peripheral nerve dysfunction. In particular, the deletion of serine 63 (S63del) in the extracellular domain of P0 results in P0 misfolding and ER retention, with the activation of the unfolded protein response (UPR).
|The WT and the S63C variants of P0 are efficiently transported at the cell surface as shown by confocal laser scanning microscopy. The disease-causing S63del mutant of P0 is in contrast retained in the ER as shown by its co-localization with the ER marker CNX|
This collaborative project reveals that the dislocon component Derlin2 controls proteasomal degradation of disease-causing P0 S63del via ER-associated degradation. Administration of N-Acetyl-D-Glucosamine (GlcNAc), a putative regulator of protein biogenesis, ameliorates S63del nerve myelination ex vivo. In contrast, Derlin2 ablation results in intracellular accumulation of misfolded P0 S63del and exacerbates cellular stress and disease status. Notably, ablation of Derlin2 affects maintenance of normal peripheral nervous system in vivo, thus unveiling the protective role of ER quality control pathways in peripheral nerve biogenesis. All in all, these results underlie the importance of ERAD in the control of ER homeostasis in Schwann cells and in the maintenance of myelin integrity. They highlight proteostatic modulation as a therapeutic intervention to treat UPR-related neuropathies.
Volpi VG, Ferri C, Fregno I, Del Carro U, Bianchi F, Scapin C, Pettinato E, Solda T, Feltri ML, Molinari M, Wrabetz L, D’Antonio M.
PLoS Genet. 2019 Apr 17;15(4):e1008069. doi: 10.1371/journal.pgen.1008069. eCollection 2019 Apr.