Deep Molecular Analysis of Lesion Formation in NMOSD

Neuromyelitis Optica Spectrum Disorders (NMOSD) are autoimmune diseases of the central nervous system which are characterized by the presence of pathogenic autoantibodies in the serum of most affected patients. During onset attack or relapse, these autoantibodies gain access to spinal cord, optic nerves, or brain. Here, they bind to the water channel aquaporin 4 on astrocytes, which may result in two fundamentally different types of pathological changes. In most parts of the central nervous system, the antibody binding initiates the destruction of astrocytes, and subsequent further tissue injury characterized by dysfunction and death of neurons and myelin-forming oligodendrocytes. This may cause permanent blindness or paralysis of affected patients. However, there are parts of the brain (such as the area postrema) where the binding of the pathogenic antibodies does not have such severe consequences. Instead, the aquaporin 4-expressing cells essentially survive, and the lesions resolve. What makes the area postrema so special? Which are the molecular inhibitors of cell destruction in the area postrema and, likewise, which are the drivers shaping the formation of destructive lesions in other sites of the central nervous system? We plan to answer these questions. To do that, we will use the most modern molecular and histological analysis tools to identify the molecular pathways involved in the formation of these different lesion types. This approach will not only help us to understand lesion evolution in NMOSD at unprecedented depth, but might reveal novel targets for therapeutic intervention.