As outlined above, astrocyte reactivity should in the first instance be regarded as an ancient, conserved and normal physiological response that evolved to protect neural tissue, maintain tissue homeostasis and preserve neurological functions after diverse insults. When trying to understand disease mechanisms, normal reactive astrocyte subtypes and states should not be conflated with disease states that are caused by cell-autonomous astrocyte dysfunctions, which can contribute to neuronal dysfunction and neurodegeneration either prior to astrocyte reactivity or by inducing abnormal reactivity states (Key Figure, Figure 2G,H). For example, gene mutations or polymorphisms in HD [58, 86], familial ALS [55], Alexander disease [87], AD with APOE4 polymorphism [56], infections with prions [68] or viruses [88], or exposure to environmental toxins [25], can all directly lead to disease-induced cell-autonomous astrocyte dysfunctions that worsen the outcomes of disorders or disorder models. Such cell-autonomous astrocyte dysfunctions can begin before detectable evidence of astrocyte reactivity (Key Figure, Figure 2H), as seen for example in a mouse model of HD, where early dysregulation of extracellular K+ homeostasis contributed to neuronal hyperexcitability and symptom onset [86]. Alternatively, disease-induced
