In order to promote myelin repair in MS, recent high-throughput screening efforts have identified a number of myelin regenerative compounds ( Deshmukh et al., 2013 Mei et al., 2014 Najm et al., 2015 Samanta et al., 2015). Additionally, it is thought that the microenvironment may also modify the epigenetic regulation of OPCs to alter transcriptional programs necessary for differentiation during development and after demyelination ( Liu et al., 2016a, 2016b Moyon et al., 2016 Huynh et al., 2014). Remyelination is an inefficient process in MS, which is likely due to an inhibitory microenvironment that prevents oligodendrocyte precursor cells (OPCs) from terminally differentiating into myelinating oligodendrocytes ( Chang et al., 2002 Huang and Franklin, 2011 Kuhlmann et al., 2008 Wolswijk, 1998). However, while it seems intuitive that remyelination plays a crucial role in preserving axonal integrity and restoring neuronal function in an inflammatory condition like MS, direct evidence is lacking. The importance of myelin in the developing CNS is further illustrated by recent findings demonstrating that oligodendrocytes provide critical metabolic support to neurons ( Fünfschilling et al., 2012 Lappe-Siefke et al., 2003 Lee et al., 2012). As a crucial accessory to the functional nerve-fiber unit, the myelin sheath provides multiple-layers of concentric membrane, which act to maximize the speed and reduce the energy demands of action potentials. To date, there are no therapeutic interventions that directly prevent neuronal degeneration, especially as the precise mechanisms underlying degeneration remain undetermined ( Bjartmar and Trapp, 2003 Simons et al., 2014). Over the course of the disease, demyelinated axons undergo irreversible degeneration, which correlates with progression and results in permanent disability-events that are pathological hallmarks of progressive MS ( Trapp et al., 1998 Bitsch et al., 2000 Bjartmar et al., 2003 Franklin et al., 2012 Kuhlmann et al., 2002 Lovas et al., 2000 Tallantyre et al., 2009 Trapp and Stys, 2009 Singh et al., 2013 Sorbara et al., 2014). Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.ĭemyelination in multiple sclerosis (MS) results from an aberrant immune response that targets the myelin sheath in the central nervous system (CNS) ( Franklin, 2002). Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. ![]() We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. ![]() ![]() Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Demyelination in MS disrupts nerve signals and contributes to axon degeneration.
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