The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP
Sarrabeth Stone, Shuangchan Wu, Klaus-Armin Nave, Wensheng Lin
Sarrabeth Stone, Shuangchan Wu, Klaus-Armin Nave, Wensheng Lin
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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 7

Inactivation of PERK and ATF6α caused delocalization of cathepsin D from the lysosome in mature oligodendrocytes at P45.

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Inactivation of PERK and ATF6α caused delocalization of cathepsin D from...
(A) Real-time PCR analysis showed that the levels of SEZ6L2 and GNPTAB were comparable in the optic nerve of WT mice, PERK-KO mice, ATF6α-KO mice, and double-KO mice at P21. N = 3 animals. (B) Real-time PCR analysis showed that the levels of SEZ6L2 and GNPTAB were significantly reduced in the optic nerve of double-KO mice compared with WT mice, PERK-KO mice, and ATF6α-KO mice at P28. N = 4 animals. (C) Real-time PCR analysis showed that the level of SEZ6L2 was significantly reduced in the optic nerve of double-KO mice compared with WT mice, PERK-KO mice, and ATF6α-KO mice and that the level of GNPTAB was significantly reduced in the optic nerve of double-KO mice compared with WT mice and PERK-KO mice at P45. N = 4 animals. (D–W) CC1, LAMP1, and cathepsin D triple labeling revealed significant colocalization of LAMP1 and cathepsin D in oligodendrocytes of WT mice, PERK-KO mice, and ATF6α-KO mice at P45. Conversely, there was little to no colocalization of LAMP1 and cathepsin D in oligodendrocytes of double-KO mice. N = 4 animals. Scale bars: 10 μm. Error bars represent mean ± SD. Statistical analyses were done with a 1-way ANOVA with Tukey’s posttest; *P < 0.05.