Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells
| Autor: | Simon Lovestone, C.Hugh Reynolds, Donna Latimer, Daniel R. Davis, Brian H. Anderton, Jean-Marc Gallo, Diane Hanger, Sandrine Mulot, Betina Marquardt, Silvia Stabel, James R. Woodgett, Christopher C.J. Miller |
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| Rok vydání: | 1994 |
| Předmět: |
Mitogen-Activated Protein Kinase 3
Tau protein tau Proteins macromolecular substances Protein Serine-Threonine Kinases Transfection General Biochemistry Genetics and Molecular Biology Cell Line MAP2K7 Glycogen Synthase Kinase 3 Alzheimer Disease GSK-3 mental disorders Animals Humans Phosphorylation Mammals Mitogen-Activated Protein Kinase 1 Neurons COS cells biology MAP kinase kinase kinase Kinase Glycogen Synthase Kinases Brain Protein-Tyrosine Kinases Molecular biology Rats Calcium-Calmodulin-Dependent Protein Kinases biology.protein Mitogen-Activated Protein Kinases General Agricultural and Biological Sciences |
| Zdroj: | Current Biology. 4:1077-1086 |
| ISSN: | 0960-9822 |
| Popis: | Background: Paired helical filaments (PHFs) are a characteristic pathological feature of Alzheimer's disease; their principal component is the microtubule-associated protein tau. The tau in PHFs (PHF-tau) is hyperphosphorylated, but the cellular mechanisms responsible for this hyperphosphorylation have yet to be elucidated. A number of kinases, including mitogen-activated protein (MAP) kinase, glycogen synthase kinase (GSK)-3 α , GSK-3 β and cyclin-dependent kinase-5, phosphorylate recombinant tau in vitro so that it resembles PHF-tau as judged by its reactivity with a panel of antibodies capable of discriminating between normal tau and PHF-tau, and by a reduced electrophoretic mobility that is characteristic of PHF-tau. To determine whether MAP kinase, GSK-3 α and GSK-3 β can also induce Alzheimer's disease-like phosphorylation of tau in mammalian cells, we studied the phosphorylation status of tau in primary neuronal cultures and transfected COS cells following changes in the activities of MAP kinase and GSK-3. Results Activating MAP kinase in cultures of primary neurons or transfected COS cells expressing tau isoforms did not increase the level of phosphorylation for any PHF-tau epitope investigated. But elevating GSK-3 activity in the COS cells by co-transfection with GSK-3 α or GSK-3 β decreased the electrophoretic mobility of tau so that it resembled that of PHF-tau, and induced reactivity with eight PHF-tau-selective monoclonal antibodies. Conclusion Our data indicate that GSK-3 α and/or GSK-3 β , but not MAP kinase, are good candidates for generating PHF-type phosphorylation of tau in Alzheimer's disease. The involvement of other kinases in the generation of PHFs cannot, however, be eliminated. Our results suggest that aberrant regulation of GSK-3 may be a pathogenic mechanism in Alzheimer's disease. |
| Databáze: | OpenAIRE |
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