John started out by adding together two elements present in MS lesions: various immune molecules and glial cells called astrocytes. One change stood out: the cytokine TGFβ1 caused astrocytes to make Jagged1. This ligand for Notch (which is present on oligodendrocytes) was also made by reactive astrocytes in MS lesions. Addition of Jagged1 to cultured oligodendrocytes inhibited process outgrowth, which is one measure of maturation.
During development, Jagged1 keeps oligodendrocytes in an immature state so that they can migrate to cover entire axons before beginning the sedentary process of myelination. The induction of this pathway in brain lesions may be an attempt to generate a larger pool of oligodendrocyte precursors, or it may be an unfortunate carryover from development of the immune system.
Whatever the underlying logic, the Notch pathway represents a possible target for MS treatment. The initiating immune cascades are another possible target, although here the details remain sketchy. “If we understood the actual triggers to inflammation in MS,” says John, “we would be halfway to a cure.” ▪