Modelling Neurodegeneration and Remyelination Processes: Past, Present, and Prospectives for Drug Discovery

Dear Colleagues,

Brain white matter is formed primarily of myelinated axons i.e. nerve fibers, which are extensions of nerve cells, sheathed by myelin. The latter transmit signals at a higher velocity than non-myelinated nerves. The destruction of the central nervous system (CNS) myelin sheath can occur as a consequence of injury, viral infection or diseases, such as multiple sclerosis (MS). Loss of the myelin sheath affects motor, sensory, and cognitive abilities by leading to neurodegeneration unless myelin is repaired by a natural process named remyelination. Remyelination occurs spontaneously in healthy adults by stimulating the proliferation of cells able to give rise to oligodendrocytes (OLs) that synthesize myelin in the CNS. Current research in the field is focused on clarifying the molecular details of how OLs are recruited, contact and wrap axons in healthy and in disease environments. Accumulating evidence shows that OPC proliferation, migration to and/or differentiation at the lesion site can be impaired by the inflammatory environment and changes in the mechano-chemical properties of axons, especially during secondary phases of MS. Remyelination process can be stimulated by small chemical molecules in vitro and in animal models of MS, but  none of the active drugs identified in phenotypical screens has as yet arrived at the clinic, mainly due to the difficulty of characterizing drug effects in preclinical studies, due to the high complexity of the axon-glia interaction system  system and OLs. Reductionist approaches have been undertaken recently based on the evidence that OLs can recognise and engage axons also when the latter are inactive. The possibility to study the mechanical and chemical properties guiding axon-oligodendroglia interactions by uncoupling indirect (neuronal) from direct (oligodendroglia) effects during myelination in vitro have opened the possibility to characterize several aspects of remyelination previously unclear and to develop novel strategies in drug discovery. Many questions remain opened. How oligodendroglia cells recognise the demyelinated area? Are there neuronal factors stimulating OPC differentiation? How many cell types participate in remyelination?  All remyelination drugs identified act similarly in their remyelination properties? Which are the best cellular models for drugs discovery for remyelination studies? Are there novel animal models for demyelination disease?

Paper that discuss these topics are invited to be submitted for this special issue

Dr. Antonella Ragnini-Wilson
Guest Editor

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• remyelination
• myelin
• oligodendroglia differentiation
• neurodegeneration