Rodriguez et al.10 identified dying back of OL processes with preserved cell bodies in acute MS lesion biopsies, as had first been described in early phases of demyelination in the cuprizone mouse model by Ludwin et al.41. Such retraction would impair participation in any recovery response. We reproduced this potentially reversible response by human adult mature OLs in both dissociated cell culture and microfibre ensheathment assays, using an array of insults implicated in MS pathogenesis including the pro-inflammatory molecules interferon (IFN)-γ and tumor necrosis factor (TNF)-α, the excitatory neutrotransmitter glutamate, and metabolic stress conditions involving nutrient deprivation and low glucose19,42. RNA sequencing revealed that process retraction can occur via a number of distinct mechanisms, reflecting the mediators of injury (Fig. 2). First, IFNγ or TNF-α induced the STAT1/IRF-1 signaling pathway; this pathway has been shown to impair process outgrowth in 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
