The Integrated UPR and ERAD in Oligodendrocytes Maintain Myelin Thickness in Adults by Regulating Myelin Protein Translation

Abstract

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocytespecific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.

Oligodendrocyte-Specific Mechanisms of Myelin Thinning: Implications for Neurodegenerative Diseases

“…Similar to these findings (Wu et al, 2020), another study showed that myelin thinning and behavioral inflexibility (touch screen based learning tasks) occurred without changes in axon number and diameter, confirming that myelin pathology precedes axonal pathology in demyelinating diseases (Silva et al, 2019). Although the PLP and Sel1L double knockout worsened the detrimental effects on myelin, a reduction of myelin basic protein (MBP) was also observed from 10 weeks of age, resulting in myelin thinning (Wu et al, 2020). Likewise, a previous study reported that abnormal distribution of MBP (rather than total MBP protein levels) contributes to myelin thinning (Silva et al, 2019).…”

“…However, astrocytes are believed to be less sensitive to UPR disruption (Murao and Nishitoh, 2017), although a recent study showed that the vesicular release of thrombin protease inhibitor from perinodal astrocytes is involved in myelin thinning (by preventing the attachment of myelin to axons) and in reduced conduction speed in optic nerves of mice (Dutta et al, 2018). Whether astrocytes were involved in microglia recruitment in this study (Wu et al, 2020) remains untested. However, the UPR is not unique to MS; rather it is a pathological hallmark of Alzheimer's, Parkinson's, and Prion diseases (García-González et al, 2018), suggesting that these neurodegenerative diseases share similar pathological pathways.…”

“…Notably, there was no difference between male and female mice in the damage caused by Sel1L deficiency. Importantly, the myelin thinning reported by Wu et al (2020) was attributed to the reduction in myelin protein translation, not as a consequence of remyelination or regeneration. Specifically, a myelin protein called proteolipid protein (PLP) was found to be vital in the process of myelin thinning.…”

“…This is because in immature oligodendrocytes, MBP is largely localized in the cell body, while in mature oligodendrocytes, MBP is distributed to membranous processes contributing to myelin formation (Silva et al, 2019). These observations (Silva et al, 2019;Wu et al, 2020) suggest that myelin thinning is not exclusive to the loss of a single class of myelin proteins (e.g., PLP), but rather the reduction of multiple myelin proteins (e.g., PLP, MBP) contribute to myelin thinning. Since PERK activation in oligodendrocytes has been reported in many demyelinating diseases (e.g., MS) of the CNS, it poses a challenge for researchers to distinguish between myelin thinning caused by PERK activation and thinner myelin generated by remyelination following demyelination.…”

“…In addition to the association of PERK activation in myelin thinning in Sel1L deficient mice (Wu et al, 2020), the disruption of PI3K-AKT-mTORC signaling (which is the downstream of the PERK-eIF2α pathway and also involved in protein translation) in oligodendrocyte function and myelination has been demonstrated in many studies (Zhang et al, 2003;Sherman et al, 2012;Lebrun-Julien et al, 2014;Jiang et al, 2016). The kinase Akt (a serine/threonine kinase) expression in oligodendrocytes leads to enhanced myelination FIGURE 1 | Schematic of the role of the unfolded protein response in myelin structure.…”