MS is a chronic inflammatory demyelinating neurological disorder with about 2.5M affected people worldwide and is the major cause of disability in young adults not related to accidents. It is characterized by the damage to a particular cell type in our brain, oligodendrocytes, and the loss of the fatty substance myelin they produce – which we call demyelination. This myelin is tightly wrapped around the long fibers (called axons) that connect our nerve cells in the brain and has two functions; it provides nutrients to the axons and also speeds up the conduction of nerve impulses along them. As a result, its loss leads to reduced function and then degeneration of the axon. This in turn causes the disability that characterizes progressive MS, for which there are currently no treatments.
Repair mechanisms within human brains initially cope with the damage caused by MS and replace the lost myelin– a process that we call remyelination. However as the years go by, the remyelination capacity of the brain decreases and persistent areas of myelin loss – called demyelinated lesions – remain. A key question for those trying to develop new treatments for progressive MS is therefore: What is the balance between damage and repair in the brain of each person affected with MS? Only by knowing this can treatments be targeted at the right process in the patient. However, up to now, we know little about how oligodendrocytes change with damage and repair in MS and between different people.
In order address this gap of knowledge, in this project, I used a powerful technology called single-nuclei RNA-sequencing allowing me to analyse the pattern of gene expression in thousands of individual brain cells within a frozen tissue sample from human brains post mortem. With this, I discovered which cells were present and how they function first in the healthy human brain, and then whether these were different in normal and damaged areas MS brain. This helped me discover clues about how oligodendrocyte changes link with damage and repair.
By gaining a better knowledge about oligodendrocytes in our brain, the work of this project was a key step towards understanding the cellular changes that are happening in MS. The results are important for two reasons. First, this understanding will enable rational approaches to drug discovery based on targeting both the damage-causing mechanisms that are responsible for the selective loss of some oligodendrocytes and the repair mechanisms required to restore an optimal balance of them. Second, the innovative technology that I have established in our lab will enable far greater accuracy in the pathological analysis of MS brain that is possible by current microscopy-based methods. This has now led to a far bigger current study that will in turn lead to greatly improved knowledge as to the variation in MS between different patients.
