Myelination represents a key evolutionary event associated with the development of large and complex nervous system in hinged-jaw vertebrates.
In the central nervous system (CNS), myelin is formed by oligodendrocytes that derive from oligodedrocyte progenitor cells (OPCs). CNS myelin in good health is crucial for appropriate axonal function given that it:
- enables saltatory conduction of action potentials
- provides axons with trophic support, including energy substrates such as lactate
- is crucial for appropriate axonal transport.
Several CNS diseases are characterized by myelin alterations/loss (demyelination). These include leukodystrophies, periventricular leukomalacia, multiple sclerosis, and spinal cord injury. Leukodystrophies are congenital myelin disorders characterised by genetic abnormalities resulting in failure of proper myelin sheath formation (hypomyelination) and/or maintenance (dysmyelination). Periventricular leukomalacia is the commonest form of ischaemic injury in premature infants leading to damage of oligodendroglial cells. Multiple sclerosis is a chronic inflammatory CNS disorder characterized by disseminated demyelination and axonal loss. Demyelination is also a feature of spinal cord injury, as even after the most severe insults, certain axons survive, but become demyelinated and exhibit consequent alterations of the conduction.
Restoring myelin in these pathologies may prevent axonal loss and permanent neurological handicap. While regenerative approaches will depend on the type of pathology, understanding the mechanisms of myelin generation/regeneration will be crucial in designing such therapies.
Mechanisms underlying the generation of mature oligodendrocytes by OPCs and subsequent myelin formation during the development and following myelin lesions have been a subject of many studies. However, bioenergetic needs of OPCs remain scarcely characterized. The aim of my research is to understand bioenergetic requirements of OPCs during myelin generation.