ERA-NET NEURON: Investigation of the neuroinflammatory basis of the human type I

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Aicardi-Goutières syndrome (AGS) is a cause of very severe brain disease in children. A lot ofevidence exists to indicate that this brain damage is due to an inflammatory process involving theproduction of a chemical called interferon. Interferon is normally produced by cells in response toinfection by a virus, and some children with AGS are initially misdiagnosed as having a viral-related disease because of the close clinical overlap of these states. In contrast to the production of interferonsecondary to virus, in AGS an excess of interferon occurs due to a primary genetic defect. Because ofthe severity of the condition there is an urgent need to develop new treatments for AGS. We think thisshould be possible if we better understand how the responsible genetic changes drive interferonproduction.We intend to use the very latest genetic and cell technologies to understand how brain cells aredamaged by inflammation in AGS. AGS is rare, and few parents feel able to agree to post-mortem iftheir affected child dies. However, a family with affected twin girls has generously donated the brain ofone of their very recently deceased daughters. This almost unique resource will allow us to studyhuman neurological tissue in more detail than ever before, and using new techniques which have notbeen available previously. Additionally, we are going to make use of state-of-the-art methods forproducing 'brain cells' in a test-tube - derived from cells of patients with AGS, so that we can studybrain tissue in the context of several different genetic sub-types of AGS. We also intend to analyse astrain of mouse which has changes in one of the AGS-related genes as another approach to trying tounderstand the human disease.Although AGS is rare, the study of the genes and the proteins related to the disease has become ofvery high scientific importance - partly because of the involvement of these genes / proteins in howthe body reponds to infection by HIV-1 (the virus that causes AIDS), and also because of an overlapwith diseases where the body attacks itself - so-called autoimmunity. Thus, not only will our work be relevant to the children and families affected by this dreadful condition, it may also have relevance for a much wider set of human medical disorders.