Healthy myelin is a crucial determinant of axonal function, and in the central nervous system (CNS) it is formed by oligodendrocytes. Because oligodendroglial/myelin dysfunction is a feature of many neurological diseases, understanding the mechanisms underlying myelination, myelin maintenance, and myelin regeneration is of great importance.

Alterations of energy homeostasis in the CNS have been described as a potential driver of neurodegeneration under several pathological settings, including multiple sclerosis (MS). These alterations likely contribute to oligodendroglial dysfunction because the generation and maintenance of myelin imply a high energy demand. Yet, energy metabolism of oligodendroglia during (re)myelination remains poorly explored.

While glucose is the main energy fuel for all cells, monocarboxylates (lactate and ketone bodies) represent important alternative energy sources for the brain. Import/export of monocarboxylates requires monocarboxylate transporters (MCTs). MCT2 is the highest affinity monocarboxylate transporter, and its expression in the brain has been associated mostly with neurons. However, recent gene expression studies have shown the expression of MCT2 mRNA on oligodendrocytes and their progenitors. The aim of my thesis is to investigate the effect of oligodendroglia-specific MCT2 loss of function on myelin generation, maintenance, and regeneration in the CNS. In this talk, I will mostly focus on myelin maintenance and show that MCT2 deletion in myelinating oligodendrocytes leads to demyelination in absence of oligodendroglial death, associated with alterations of fatty acid synthesis.