Loss of central nervous system myelin is a hallmark of debilitating neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. Myelin is required for neuronal homeostasis, without which progressive neurological dysfunction occurs. Oligodendrocytes generate myelin by wrapping their processes around axons in the central nervous system. During neurodegenerative diseases, oligodendrocytes sustain damage and lose their myelin, dubbed demyelination. The loss of myelin was thought to be fatal for oligodendrocytes, and the generation of new myelin was thought to require newly differentiated oligodendrocytes. Recently, however, oligodendrocytes have been observed to survive damage and even make new myelin thereafter, albeit with reduced efficacy. However, the mechanisms behind this survival and the factors influencing their remyelination capacity remain unclear.  This project aims to identify biomarkers of surviving oligodendrocytes, assess the role of surviving oligodendrocytes in remyelination, and explore therapeutic strategies to enhance their functionality.

I will utilize zebrafish models of myelin damage and human multiple sclerosis tissue to identify biomarkers and pathways that may influence the fate of oligodendrocytes surviving demyelination. Through following individual oligodendrocytes in zebrafish and using the HaloTag dyeable fluorescence system to pulse-chase oligodendrocytes, I will characterise the role of surviving oligodendrocytes in vivo. Furthermore, using CRISPR and pharmacological approaches, I will manipulate surviving oligodendrocytes, aiming to improve their remyelination capacity. By leveraging innovative imaging tools and cross-species analyses, this research has the potential to transform our understanding of oligodendrocytes in disease and contribute to novel therapeutics.