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

Shuangchan Wu, Wensheng Lin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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; Sel1LloxP/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; Sel1LloxP/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/CreERT; Sel1LloxP/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.

Original languageEnglish (US)
Pages (from-to)1360-1376
Number of pages17
JournalGlia
Volume71
Issue number5
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
We thank Dr Ling Qi (University of Michigan, Ann Arbor, MI) for providing the mice. We thank Dr Brian Popko (Northwestern University, Chicago, IL) for providing the mice. We thank Dr M. A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, MD) for providing the antibody against aspartoacylase. This study was supported by grants from the National Institutes of Health (NS094151 and NS105689) to Wensheng Lin. Sel1L loxP/loxP PLP/CreER T

Publisher Copyright:
© 2023 Wiley Periodicals LLC.

Keywords

  • ERAD
  • Schwann cell
  • Sel1L
  • UPR
  • myelin
  • oligodendrocyte

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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