Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia

Abstract

Myelin is vital to the proper function of the nervous system. Oligodendrocytes in the CNS and Schwann cells in the PNS are the glial cells responsible for generating the myelin sheath. Myelination requires the production of a vast amount of proteins and lipid-rich membrane, which puts a heavy load on the secretory pathway of myelinating glia and leaves them susceptible to endoplasmic reticulum (ER) stress. Cells respond to ER stress by activating the unfolded protein response (UPR). The UPR is initially protective but in situations of prolonged unresolved stress the UPR can lead to the apoptotic death of the stressed cell. There is strong evidence that ER stress and the UPR play a role in a number of disorders of myelin and myelinating glia, including multiple sclerosis, Pelizaeus-Merzbacher disease, Vanishing White Matter Disease, and Charcot-Marie-Tooth disease. In this review we discuss the role that ER stress and the UPR play in these disorders of myelin. In addition, we discuss the progress that has been made in our understanding of the effect genetic and pharmacological manipulation of the UPR has in mouse models of these disorders and the novel therapeutic potential of targeting the UPR that these studies support. This article is part of a Special Issue entitled SI:ER stress.

Trial registration: ClinicalTrials.gov NCT02423083.

Keywords: ER stress; Myelin; Oligodendrocytes; Schwann cells; Unfolded protein response.

Copyright © 2016 Elsevier B.V. All rights reserved.

Figures

Figure 1

Oligodendrocyte and Schwann cell electron micrographs. (A) False color electron microscopy image and (C) schematic of a myelinated axon in the CNS with an oligodendrocyte process (blue) forming the myelin sheath. (C) Oligodendrocytes will myelinate multiple axon segments in the CNS. B) False color electron microscopy image and (D) schematic of a myelinated axon in the PNS. The Schwann cell body (green) engulfs the axon and will only produce the myelin sheath for a single axon segment.

Figure 2

Myelinated axon domains and metabolic support of axons by oligodendrocytes. Contact with oligodendrocytes is necessary for clustering of Na+ channels at nodes and K+ channels at juxtaparanodes, which are required for fast saltatory conduction of action potentials. Oligodendrocytes also metabolically support axons by shuttling lactate through oligodendrocyte expressed MCT-1 into the periaxonal space where it is taken up into the axon through the neuron expressed MCT-2.