Abstract:

The production, transport and integration of myelin components into the membrane during development is a highly coordinated and regulated process that relies heavily on the endoplasmic reticulum (ER), a sub-cellular organelle that is the principal site of membrane assembly. Ribosomes on the rough ER allow translation of proteins such as proteolipid protein (PLP) (comprising 50% of total myelin protein) prior to correct folding, post-translational modifications and eventual complexing with nascent smooth ER-synthesised lipids. We hypothesise that oligodendrocytes may make use of a specialised UPR during developmental myelination to cope with exceptional synthetic demand in a manner similar to that employed by differentiating B lymphocytes, where the three arms of the UPR are differentially activated and there is a notable suppression of the PERK pathway. Such a strategy would probably be beneficial in the instance of high protein and membrane manufacture, such as myelination, since PERK signalling is known to result in a significant and global reduction in protein translation. Suppression of this arm, in conjunction with the increase in molecules that improve both the capacity and efficiency of the ER, afforded by signalling through ATF6 and IRE1, can only be of benefit during a period of such intense bioactivity. The question of whether or not activation of the IRE1 and ATF6 arms of the UPR can be boosted therapeutically in an effort to promote remyelination in diseases such as MS, merits further investigation.