Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults

Abstract

Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1L loxP/loxP mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS. Because Sel1L is deleted in myelinating cells of CNP/Cre; Sel1L loxP/loxP mice starting at very early stage of differentiation, it is impossible to rule out the possibility that the adult-onset myelin abnormalities in these mice results from developmental myelination defects caused by Sel1L knockout in myelinating cells during development. Thus, using an inducible Sel1L knockout mouse model (PLP/CreER T ; Sel1L loxP/loxP mice) that has normal, intact myelin and myelinating cells in the adult CNS and PNS prior to tamoxifen treatment, we sought to determine if Sel1L knockout in mature myelinating cells of adult mice leads to myelin abnormalities in the CNS and PNS. We showed that Sel1L knockout in mature myelinating cells caused ERAD impairment, ER stress and UPR activation. Interesting, Sel1L knockout in mature oligodendrocytes impaired their myelinating function by suppressing myelin protein translation, and resulted in progressive myelin thinning in the adult CNS. Conversely, Sel1L knockout in mature Schwann cells led to Schwann cell apoptosis and demyelination in the adult PNS.These findings demonstrate the essential roles of ERAD in mature myelinating cells in the adult CNS and PNS under physiological conditions.

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

“…XBP1s appears to exert its protective function mostly via up-regulation of genes involved in ER proteostasis pathways such as ERAD. This is particularly intriguing since we and others have recently shown that a functional ERAD is required to maintain myelin in adult glial cells, 56,58 and that impairment of ERAD severely worsens myelin defects and neurophysiological parameters in CMT1B. 56 Mutant misfolded P0 proteins are in fact degraded via the ERAD-proteasome pathway, 56,59 and impairment of ERAD via Schwann cell specific ablation of Derlin-2 exacerbated the UPR and the overall phenotype of S63del mice.…”