Remyelination Failure Potentiates Axon Loss and Impairs Motor Function following Cuprizone Demyelination

Multiple sclerosis (MS) is characterized by inflammatory demyelination,axonal degeneration and limited regeneration ofmyelin. Increasingly, axon loss has been linked to progressivedisability, but its underlying mechanisms remain unclear. Oligodendrocytessupport axonal survival in the healthy nervoussystem but there is currently little causative evidence demonstratingthat remyelination is sufficient to increase axonal survival.Previously, we demonstrated that MYRF expression innew oligodendrocytes was essential for remyelination and afailure to express MYRF was linked with remyelination failurein MS. Here, we use an inducible Myrf knockout from OPCs(Myrf ICKO) following cuprizone/rapamycin intoxication toexplicitly determine if remyelination is sufficient to preserveaxons following demyelination. Myrf ICKO prevents the accumulationof new oligodendrocytes and results in a failure toremyelinate even seven weeks after cuprizone/rapamycin demyelination.Remyelination failure resulted in no overt changesin astrogliosis or inflammation but increased oxidative stresswithin the corpus callosum. A lack of oligodendrogenesis andremyelination left axons more prone to degeneration and subsequentlyimpaired initial motor behavioural recovery. Therefore,improving remyelination is sufficient to ameliorate axon lossfollowing inflammatory demyelination and will likely be an effectivetherapeutic strategy to attenuate axon loss in MS. Thisnovel model will allow the testing of drug candidates for axonalprotection after demyelination.