Closing the gap: advancing our understanding of myelination through molecular characterisation of the paranode

Myelination of neuronal axons is fundamental for rapid and efficient signal conduction, yet a detailed understanding of how the molecular contacts between the myelin sheath and axon are established remains poorly characterised. This septate-like junction, known as the paranode, forms a diffusion barrier that prevents aberrant protein translocation between the myelinated axon and the nodes of Ranvier and limits short-circuiting of the action potential. The importance of this junction is highlighted by the severe and devastating diseases that arise as a consequence of its disruption. In the nervous system, this cell-cell contact is mediated by the myelin-specific protein NF155, axon-specific proteins CNTN1 and Caspr, and interactions with specific glycosphingolipids in the plasma membrane outer leaflet. However, a molecular understanding of this multifaceted contact site, and therefore how the paranode stabilises myelination, is currently lacking. My preliminary data suggests a complex and intriguing mechanism with the potential to shift the way in which we investigate membrane-protein contacts. This proposal seeks to advance our understanding of how the healthy nervous system is myelinated through in-depth molecular characterisation of the paranodal complex and gain insight into the pathophysiology of demyelinating autoimmune neuropathies, laying the foundations for the development of new targeted treatment strategies.