Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways

• Published in: Human molecular genetics 2008-06, Vol.17 (11), p.1540-1555
• Main Authors: Tang, Guomei, Yue, Zhenyu, Talloczy, Zsolt, Hagemann, Tracy, Cho, Woosung, Messing, Albee, Sulzer, David L., Goldman, James E.
• Format: Article
• Language: English
• Subjects: Alexander Disease - genetics; Alexander Disease - metabolism; Animals; Astrocytes - metabolism; Autophagy - genetics; Biological and medical sciences; Brain - metabolism; Brain - ultrastructure; Cell Line, Tumor; Cell physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Humans; Medical sciences; Mice; Mice, Mutant Strains; Molecular and cellular biology; Mutation; Neurology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Kinase Inhibitors; Protein Kinases - genetics; Protein Kinases - metabolism; RNA, Small Interfering - genetics; Signal Transduction; TOR Serine-Threonine Kinases; Vacuoles - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn042

Glial fibrillary acidic protein (GFAP) is the principle intermediate filament (IF) protein in astrocytes. Mutations in the GFAP gene lead to Alexander disease (AxD), a rare, fatal neurological disorder characterized by the presence of abnormal astrocytes that contain GFAP protein aggregates, termed Rosenthal fibers (RFs), and the loss of myelin. All GFAP mutations cause the same histopathological defect, i.e. RFs, though little is known how the mutations affect protein accumulation as well as astrocyte function. In this study, we found that GFAP accumulation induces macroautophagy, a key clearance mechanism for prevention of aggregated proteins. This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is in part responsible for the down-regulation of phosphorylated-mTOR and the subsequent activation of autophagy. Our study suggests that AxD mutant GFAP accumulation stimulates autophagy, in a manner regulated by p38 MAPK and mTOR signaling pathways. Autophagy, in turn, serves as a mechanism to reduce GFAP levels.