Endoplasmic reticulum stress signalling in myelination
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Demyelinating conditions such as multiple sclerosis have a continued unmet need for remyelinating therapies. Myelin is a multi-lamellar membrane structure made by oligodendrocyte progenitor cells (OPCs) that is critical for saltatory conduction and neuronal health. The simultaneous ensheathment of multiple axons with myelin confers a radically increased load on the endoplasmic reticulum (ER) from which membrane proteins and lipids are made. ER stress signalling triggers a conserved, homeostatic signalling system known as the Unfolded Protein Response (UPR) which can increase ER capacity or initiate apoptosis according to stress severity. Despite recognition of the substantial synthetic demands placed on oligodendrocytes, the role of ER stress signalling and the UPR has not previously been fully investigated. In this work, cerebellar tracts were used to exemplify the temporal dynamics of myelination. The cerebellum is an eloquent anatomical region of high clinical relevance to MS and a widely-used model of myelination, however the majority of studies do not take into account the well-established heterogeneity of its parasagittal domains. Therefore this work has combined a comprehensive profile of ER stress and UPR-associated markers with respect to the developing and adult cerebellum in the cortex as well as in white matter tracts. It then investigated the function of these pathways during oligodendrocyte differentiation in vitro. UPR signalling was found to be unaltered between parasagittal domains of the cerebellum, suggesting it is not an intrinsic factor in patterned neurodegeneration as previously indicated. Distinct UPR profiles were associated with specific cell-types during development and highlighted transient, proliferative subpopulations in germinal niches of the cerebellum. Actively myelinating cerebellar tracts showed selective upregulation of ATF6 and IRE1 signalling in the absence of PERK activation. In addition, high basal expression of ATF6 and ER-resident chaperones was observed in mature oligodendrocytes, indicating the usage of a nuanced UPR. Modulators of UPR signalling were tested on differentiating OPCs in vitro and impairments to oligodendrocyte maturation were observed. Changes in myelin gene expression, however, did not correlate with UPR markers. This work supports the activation of the UPR during myelination and highlights how approaches to the study of the UPR may be challenging in current models. This work draws attention to how myelin synthesis is facilitated by the ER of oligodendrocytes which merits further study.
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