astrocyte subtypes with different functions was based entirely correlative based on evidence, and the functions of all of these genes are not known; in addition, to date, no causation testing loss- or gain-of-function experiments have directly linked any of these proposed marker genes to either ‘toxic’ or ‘protective’ functions of reactive astrocytes. Thus, the predictive value of these proposed marker genes as ‘signatures’ to identify specific astrocyte functional subtypes or states is untested and any attempts to correlate expression of some or all of these markers with potential ‘toxic’ or ‘protective’ astrocyte functions in different contexts is speculative and potentially misleading. In line with this uncertainty, studies thus far have found few, and in some cases none, of the ‘A1’ marker genes detectably expressed in various CNS neurodegenerative disorders or models including Huntington’s disease (HD) [58, 60], amyotrophic lateral sclerosis (ALS) [55], Alzheimer’s disease (AD) [56, 67], prion disease [68] and glioblastoma [23]. At present, to avoid such issues, it seems most appropriate to label molecularly-related astrocyte clusters neutrally, followed by experimental causation-testing dissection of effects attributable to specific molecules [61].
