Multiple sclerosis is characterized by inflammatory demyelination and limited remyelination in most individuals. Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability. Here, we describe two rodent models of genetic demyelination, one characterized by effective remyelination, and the other by a failure to remyelinate. By comparing these two models, we find that remyelination helps protect axons from damage and neurons from apoptosis, improves conduction and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), cumulating in phosphorylation of c-Jun. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.
