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.
Highlights
The endoplasmic reticulum (ER) is the site in eukaryotic cells in which modification and folding of membrane and secretory proteins take place [1, 2]
A previous study demonstrated that pancreatic ER kinase (PERK) is deleted in oligodendrocytes in the central nervous system (CNS) of PERKloxP/loxP cyclic nucleotide 3′-phosphodiesterase (CNP)/Cre (PERK-KO) mice and that PERK inactivation has no effect on oligodendrocytes or myelin in these mice [15]
We found that the mRNA levels of PERK and activating transcription factor 6α (ATF6α) were significantly reduced in the optic nerve of double-KO mice compared with WT mice (Figure 1A)
Summary
The endoplasmic reticulum (ER) is the site in eukaryotic cells in which modification and folding of membrane and secretory proteins take place [1, 2]. Perturbations in protein modification or folding lead to accumulation of unfolded or misfolded proteins in the ER and result in ER stress and activation of the unfolded protein response (UPR), which comprises 3 parallel branches: inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6α (ATF6α) [3,4,5]. PERK activation inhibits protein translation but stimulates the expression of genes related to macroautophagy (a bulk protein degradation process, hereafter referred to as autophagy) and genes related to ER-associated degradation (ERAD) by phosphorylating eukaryotic translation initiation factor 2α. ATF6α activation enhances the expression of ER chaperones, autophagy-related genes, and ERAD-related genes. The UPR is a major mechanism that maintains ER protein homeostasis and a major component of the cellular proteostasis network that preserves cellular proteostasis [4, 6, 7]
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