Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways.
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.
Tang
Guomei
G
Department of Pathology, Center for Neurobiology and Behavior, Center for Parkinson's Disease and Other Movement Disorders, Columbia University, New York, NY 10032, USA.
Yue
Zhenyu
Z
Talloczy
Zsolt
Z
Hagemann
Tracy
T
Cho
Woosung
W
Messing
Albee
A
Sulzer
David L
DL
Goldman
James E
JE
D038261:Alexander Disease / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D045744:Cell Line, Tumor; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014617:Vacuoles / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases