title: γ-Aminobutyric acid type A (GABAA) receptor activation modulates tau phosphorylation.
abstract: Abnormal phosphorylation and aggregation of the microtubule-associated protein Tau are hallmarks of various neurodegenerative diseases, such as Alzheimer disease. Molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. We have developed a novel live cell reporter system based on protein-fragment complementation assay to study dynamic changes in Tau phosphorylation status. In this assay, fusion proteins of Tau and Pin1 (peptidyl-prolyl cis-trans-isomerase 1) carrying complementary fragments of a luciferase protein serve as a sensor of altered protein-protein interaction between Tau and Pin1, a critical regulator of Tau dephosphorylation at several disease-associated proline-directed phosphorylation sites. Using this system, we identified several structurally distinct GABA(A) receptor modulators as novel regulators of Tau phosphorylation in a chemical library screen. GABA(A) receptor activation promoted specific phosphorylation of Tau at the AT8 epitope (Ser-199/Ser-202/Thr-205) in cultures of mature cortical neurons. Increased Tau phosphorylation by GABA(A) receptor activity was associated with reduced Tau binding to protein phosphatase 2A and was dependent on Cdk5 but not GSK3β kinase activity.
authors.affiliation: Neuroscience Center, Faculty of Pharmacy, University of Helsinki, Helsinki FIN-00014, Finland.
authors.forename: Niko-Petteri
authors.initials: NP
authors.lastname: Nykänen
authors.forename: Kai
authors.initials: K
authors.lastname: Kysenius
authors.forename: Prasanna
authors.initials: P
authors.lastname: Sakha
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Huttunen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008387:Marine Toxins; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009410:Nerve Degeneration / Q000378:metabolism*; D009447:Neuroblastoma; D010080:Oxazoles / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D000077546:Roscovitine; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008387:Marine Toxins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D011687:Purines; D011963:Receptors, GABA-A; D016875:tau Proteins; D000077546:Roscovitine; C059041:calyculin A; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C005134:juglone