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

The Study of Remyelinating Therapies in Multiple Sclerosis: Visual Outcomes as a Window Into Repair

“…Genetic models of demyelination can also allow us to disentangle whether the benefits of the candidate drug are due to remyelination or reduction of inflammatory injury. 43,44…”

Incomplete remyelination via endogenous or therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function

“…Myelin, made by oligodendrocytes enwrapping axons with lipid-rich membranes, is essential for proper central nervous system (CNS) function. Loss of oligodendrocytes and myelin -known as demyelination -induces severe delay and failure of action potential propagation 1,2 , leaves neurons and their axons vulnerable to degeneration [3][4][5] , and causes motor, sensory, and cognitive impairment 6,7 . Demyelination occurs in white and gray matter in several pathologies, including inflammatory demyelinating diseases like multiple sclerosis 8 , traumatic CNS injury 9,10 , stroke 11 , Alzheimer's disease 12 , and aging 13,14 .…”

“…Demyelination is typically followed by a period of heightened new myelin formation known as remyelination, which can restore action potential propagation and prevent neurodegeneration 2,4,5 . Remyelination is carried out by newly formed oligodendrocytes differentiating from oligodendrocyte precursor cells (OPCs) 17,18 as well as -in some instances -by oligodendrocytes that survive the demyelinating injury [19][20][21][22] .…”