title: Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease.
abstract: Protein aggregates in astrocytes that contain glial fibrillary acidic protein (GFAP), small heat shock proteins, and ubiquitinated proteins are termed Rosenthal fibers and characterize Alexander disease, a leukodystrophy caused by heterozygous mutations in GFAP. The mechanisms responsible for the massive accumulation of GFAP in Alexander disease remain unclear. In this study, we show that overexpression of both wild type and R239C mutant human GFAP led to cytoplasmic inclusions. GFAP accumulation also led to a decrease of proteasome activity and an activation of the MLK2-JNK pathway. In turn, the expression of activated mixed lineage kinases (MLKs) induced JNK activation and increased GFAP accumulation, whereas blocking the JNK pathway decreased GFAP accumulation. Activated MLK also inhibited proteasome function. A direct inhibition of proteasome function pharmacologically further activated JNK. Our data suggest a synergistic interplay between the proteasome and the SAPK/JNK pathway in the context of GFAP accumulation. Feedback interactions among GFAP accumulation, SAPK/JNK activation, and proteasomal hypofunction cooperate to produce further protein accumulation and cellular stress responses.
authors.affiliation: Department of Pathology and the Center for Neurobiology and Behavior, Columbia University, 630 W. 168th Street, New York, NY 10032, USA.
authors.forename: Guomei
authors.initials: G
authors.lastname: Tang
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
authors.forename: James E
authors.initials: JE
authors.lastname: Goldman
mesh_terms: D038261:Alexander Disease / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D048670:MAP Kinase Kinase 4; D046988:Proteasome Endopeptidase Complex