neurons and regulate glycolysis - the major source of of ATP in mature OLs which contributes to protein and lipid production needed for myelin biosynthesis. Some studies have also proposed that TNFα modulates the Rho GTPase pathways regulating the cytoskeleton through the activation of the autophagy pathway, providing a link to a stress response42–44. Second, glutamate-induced few changes in gene expression, implicating a direct effect on OL processes. Third, metabolic insult-induced OL process retraction was associated with induction of the integrated stress response (ISR)42, which can either be protective or contribute to cell injury, depending on its level and duration of activation. Addition of the ISR agonist Sephin1 to cultured human OL—maintained under control conditions or exposed to ongoing metabolic stress—reduced process outgrowth42, suggesting that the ISR regulates the protein synthesis machinery required for OL process outgrowth and maintenance. Consistent with this postulate, inhibiting the ISR after stress induction enhanced OL process outgrowth42. Expression of ElF2α, a major regulator of the ISR pathway, is increased in oligodendrocytes in active MS lesions compared to levels in normal appearing white matter or control tissue42.
