Disorders of Astrocytes: Alexander Disease as a Model

• Published in: Annual review of pathology 2017-01, Vol.12 (1), p.131-152
• Main Authors: Olabarria, Markel, Goldman, James E
• Format: Article
• Language: English
• Subjects: Alexander disease; Alexander Disease - physiopathology; Animals; astrocyte; Astrocytes - pathology; Disease Models, Animal; glia; gliosis; Humans; neurodegenerative diseases; Rosenthal fibers
• ISSN: 1553-4006; 1553-4014
• DOI: 10.1146/annurev-pathol-052016-100218

Astrocytes undergo important phenotypic changes in many neurological disorders, including strokes, trauma, inflammatory diseases, infectious diseases, and neurodegenerative diseases. We have been studying the astrocytes of Alexander disease (AxD), which is caused by heterozygous mutations in the GFAP gene, which is the gene that encodes the major astrocyte intermediate filament protein. AxD is a primary astrocyte disease because GFAP expression is specific to astrocytes in the central nervous system (CNS). The accumulation of extremely large amounts of GFAP causes many molecular changes in astrocytes, including proteasome inhibition, stress kinase activation, mechanistic target of rapamycin (mTOR) activation, loss of glutamate and potassium buffering capacity, loss of astrocyte coupling, and changes in cell morphology. Many of these changes appear to be common to astrocyte reactions in other neurological disorders. Using AxD to illuminate common mechanisms, we discuss the molecular pathology of AxD astrocytes and compare that to astrocyte pathology in other disorders.