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.
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Research Article Cell biology Neuroscience

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

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

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Figure 3

Inactivation of PERK and ATF6α in oligodendrocytes led to late-onset demyelination in the CNS, and PLP deficiency attenuated myelin loss in the CNS of double-KO mice (P45).

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Inactivation of PERK and ATF6α in oligodendrocytes led to late-onset dem...
(A–F) MBP IHC revealed severe myelin loss in the spinal cord of double-KO mice compared with WT mice, PERK-KO mice, ATF6α-KO mice, and PLP-KO mice at P45. Interestingly, myelin loss was noticeably attenuated in the spinal cord of triple-KO mice compared with double-KO mice at P45. (G–O) EM analysis revealed a dramatic reduction in myelinated axons, a significant increase in the g-ratio, and a significant reduction in myelin thickness in the spinal cord of double-KO mice compared with WT mice, PERK-KO mice, ATF6α-KO mice, and PLP-KO mice at P45. Interestingly, there was a significant increase in myelinated axons, a significant reduction in the g-ratio, and a significant increase in myelin thickness in the spinal cord of triple-KO mice compared with double-KO mice at P45. (G–L, P, and Q) EM analysis revealed a few degenerating axons (red asterisk) in the spinal cord of PLP-KO mice at P45 compared with WT mice, PERK-KO mice, and ATF6α-KO mice at P45. Importantly, there was a significant increase in degenerating axons and a significant reduction in healthy-looking axons in the spinal cord of triple-KO mice compared with PLP-KO mice and double-KO mice at P45. Scale bars: 100 μm (A–F), 5 μm (G–L); N = 4 animals. Error bars represent mean ± SD. Statistical analyses were done with a 1-way ANOVA with Tukey’s posttest; *P < 0.05.