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

- Myelinating glia are particularly sensitive to ER stress.
- A number of neurological disorders display evidence of myelinating cell ER stress.
- Guanabenz and Sephin1 enhance the UPR, thereby increasing protection to ER stress.
- Guanabenz protects oligodendrocytes in mouse models of multiple sclerosis.
- Sephin1 protects Schwann cells in a mouse model of Charcot-Marie-Tooth disorder.

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.