Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Recently published
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP
Sarrabeth Stone, … , Klaus-Armin Nave, Wensheng Lin
Sarrabeth Stone, … , Klaus-Armin Nave, Wensheng Lin
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(5):e132364. https://doi.org/10.1172/jci.insight.132364.
View: Text | PDF
Research Article Cell biology Neuroscience

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP

  • Text
  • PDF
Abstract

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.

Authors

Sarrabeth Stone, Shuangchan Wu, Klaus-Armin Nave, Wensheng Lin

×

Figure 1

Mice with double deletion of PERK and ATF6α in oligodendrocytes developed a late-onset and progressive tremoring phenotype.

Options: View larger image (or click on image) Download as PowerPoint
Mice with double deletion of PERK and ATF6α in oligodendrocytes develope...
(A) Real-time PCR analysis showed that the mRNA level of PERK was significantly reduced in the optic nerve of PERK-KO mice and double-KO mice compared with WT mice and ATF6α-KO mice and that ATF6α mRNA was undetectable in the optic nerve of ATF6α-KO mice and double-KO mice (N = 4 animals). (B and C) PCR analysis showed that XBP1s was undetectable in the spinal cord of WT mice (lane 1), PERK-KO mice (lane 2), and ATF6α-KO mice (lane 3) at P21 and P45 but became moderately detectable in double-KO mice (lane 4) at P21 and P45 (N = 4 animals). (D) Double-KO mice started to show lighter body weight at P23 compared with WT mice, PERK-KO mice, and ATF6α-KO mice (N = 10 animals). (E) Mouse survival curve. (F) Latency to fall in Rotarod test (N = 10 animals). ND, not detected. Error bars represent mean ± SD. Statistical analyses were done with a 1-way ANOVA with Tukey’s posttest (A) or a 2- way ANOVA with Tukey’s posttest (D and F); *P < 0.05.
Follow JCI Insight:
Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts