Remyelination protects neurons from DLK-mediated neurodegeneration

Abstract

SummaryChronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects 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), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the 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.HighlightsCharacterization of a mouse model of demyelination without subsequent remyelinationRemyelination protects neurons from axonal damage and apoptosisMAPK and c-Jun phosphorylation are increased during remyelination failureDLK is necessary for the apoptosis of chronically demyelinated neuronsAbstract Figure