Role of sub-membranous phase separation in the regulation of myelin membrane structure and function

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Myelin is a membrane of vital importance for the function of the nervous system. It is formed by the spiral wrapping of oligodendrocyte plasma membrane around axons of the central nervous system. The result is the formation of highly abundant, tightly packed membrane stacks with unique structural properties. Noteworthy features of myelin are richness in lipid, tight packing of its components and high physical stability. Previously, myelin was thought to be non-dynamic, but it is now clear that myelination contributes to brain plasticity being modifiable by experience. For example, myelin sheaths can shrink or grow in size in adult animals. Mechanistically, it is difficult to understand how a multilayered compacted membrane stack can change its structure after its formation. Here, we will test the hypothesis that phase transitions of the myelin basic proteins (MBP) at the cytosolic membrane interface of the myelin membrane regulate this process. We have previously shown that membrane compaction is mediated by a phase transition of MBP molecules into a cohesive meshwork. In its unassembled state MBP molecules are non-interactive, whereas the assembly uncovers its strongly adhesive properties that bring negatively charged membranes closely together. Phase transitions occurring in the cytosol are an emerging field in biology, but almost nothing is known about their role in the sub-membranous space. Here, we propose to study the role of cytosolic, sub-membranous phase transitions in regulating myelin membrane structure and function. We propose that such phase separations control the generation of an adhesive liquid regulating the opening and the closing of the myelin membrane stack to allow myelin remodeling. Another important aim is the study of the role of uncontrolled phase transitions in mediating the breakdown of myelin in demyelinating diseases.