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Oligodendrocytes that survive demyelination can remyelinate, including in multiple sclerosis (MS), but how they do so is unclear. In this study, using zebrafish, we found that surviving oligodendrocytes make few new sheaths and frequently mistarget new myelin to neuronal cell bodies, a pathology we also found in MS. In contrast, oligodendrocytes generated after demyelination make abundant and correctly targeted sheaths, indicating that they likely also have a better regenerative potential in MS., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)