ALEXANDER: The astrocyte nanofilament system in Alexander disease – from molecules to function, uncovering new leads for therapy

Alexander disease (AxD) is a rare genetic brain disease with no cure. AxD patients show white matter degeneration and extensive loss of brain tissue. AxD is often diagnosed before the age of 2, sometimes in later childhood or in adults. Symptoms include mental retardation, epilepsy, muscle stiffness, and AxD leads to death. About 500 AxD cases have been reported worldwide. AxD is caused by mutations in GFAP, an astrocyte intermediate filament (nanofilament) protein. The disease starts in astrocytes, cells that control many neuronal functions and homeostatic mechanisms of the brain. However, it is not known how AxD astrocytes cause the disease, and the available animal models are imperfect. ALEXANDER consortium partners have complementary expertise, and unique technologies to determine the cellular and molecular mechanisms leading to AxD and to design future treatment strategies. We will use induced pluripotent stem cells from AxD patients to derive astrocytes, neurons, and other glial cell types and to generate brain organoids. We will also generate an AxD killifish model. We will elucidate the effects of AxD astrocytes on neurons, and other aspects of AxD pathogenesis using a range of experimental systems and approaches. We will test compounds previously identified by the consortium partners as modulators of astrocyte activation, for their ability to reduce the detrimental activation of AxD astrocytes. Our aim is to understand the pathogenesis of AxD and possibly other diseases with the maladaptive responses of reactive astrocytes as the core underlying mechanism.