Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. Unfolded protein response (UPR), which comprises 3 parallel branches, inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6α (ATF6α), is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ER-associated degradation. Here we report that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination but caused late-onset mature oligodendrocyte dysfunction and death in young adult mice. The detrimental effects of the impaired UPR on mature oligodendrocytes were accompanied by autophagy impairment and intracellular proteolipid protein (PLP) accumulation and were rescued by PLP deletion. Data indicate that PLP was degraded by autophagy and that intracellular PLP accumulation was cytotoxic to oligodendrocytes. Thus, these findings imply that the UPR is required for maintaining cellular proteostasis and the viability and function of mature oligodendrocytes in adults by regulating autophagy of PLP.
Bibliographical noteFunding Information:
We thank Kazutoshi Mori (Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan) for providing the ATF6?-KO mice. We thank Wendy Macklin (University of Colorado School of Medicine, Aurora, Colorado, USA) for sending us the PLP-KO mice. We thank M.A. Aryan Namboodiri (Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA) for providing the antibody against ASPA. We thank Alexander Gow (Wayne State University, Detroit, Michigan, USA) for providing the antibody against PLP (AA3 antibody). We thank Michael K. Lee (University of Minnesota) for purchasing and providing the antibodies against LAMP1 and cathepsin D. This study was supported by grants from the NIH (NS094151 and NS105689) to WL.
© 2020, American Society for Clinical Investigation.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural