Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants NS094151 and NS105689 to W.L. We thank Dr. Ling Qi (University of Michigan, Ann Arbor, Michigan) for providing the Sel1LloxP/loxP mice; Dr. M. A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, Maryland) for providing the antibody against aspartoacylase; Dr. Alexander Gow (Wayne State University, Detroit, Michigan) for providing the AA3 antibody against proteolipid protein; and Dr. Wendy Macklin (University of Colorado School of Medicine, Aurora, Colorado) for sending us the PLP KO mice. The authors declare no competing financial interests. Correspondence should be addressed to Wensheng Lin at firstname.lastname@example.org. https://doi.org/10.1523/JNEUROSCI.0604-20.2020 Copyright © 2020 the authors
- Myelin thickness
- Protein translation
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural