The past decade has witnessed a burst of speculation and data about how astrocyte dysfunction contributes to the phenotypes of the well known neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, as well as other types of disorders such as epilepsies and multiple sclerosis (Rempe and Nedergaard, 2010). However, these are complex syndromes that likely represent combined abnormalities of neurons, glia, and immune cells. The clearest example of astrocytes acting as the primary culprit in disease is Alexander disease, which is caused by dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (for an extensive review, see Brenner et al., 2009). Although this disorder is quite rare, the extent to which we can understand how astrocyte function is impaired in Alexander disease, and the strategies we can devise to restore astrocyte function, will have significant implications for how we deal with the many more common neurological diseases that confront us. The purpose of this review is to introduce the wider neuroscience audience to the unique research opportunities posed by this disease.

The first recognized patient was a 16-month-old boy who died after a progressive course that included megalencephaly, hydrocephalus, and psychomotor delays (Alexander, 1949). Pathology revealed abundant astrocytic accumulations of eosinophilic cytoplasmic inclusions, recognized by neuropathologists as Rosenthal fibers (after the 19th century German pathologist who first described them in the context of an old astrocyte scar; Rosenthal, 1898) (for review, see Wippold et al., 2006) (Fig. 1). During the subsequent 15 years, additional individuals with similar pathology were reported, and in 1964 Friede suggested that these all represented a single disease, and recommended they be named after Alexander. Although the initial finding of prominent aggregates in astrocytes prompted Alexander himself to suggest that this might represent a primary disorder of astrocytes, it was the discovery of the genetic basis for the disease that established Alexander disease as a primary disorder of this major CNS cell type (Brenner et al., 2001).