Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-08, Vol.95 (16), p.9637-9641
• Main Authors: Takashima, A, Murayama, M, Murayama, O, Kohno, T, Honda, T, Yasutake, K, Nihonmatsu, N, Mercken, M, Yamaguchi, H, Sugihara, S, Wolozin, B
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer's disease; Brain - enzymology; Brain - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Chromatography, Affinity; Enzymes; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Infant, Newborn; Membrane Proteins - isolation & purification; Membrane Proteins - metabolism; Middle Aged; Mutation; Neurology; Precipitin Tests; Presenilin-1; Proteins; Substrate Specificity; tau Proteins - metabolism
• ISSN: 0027-8424; 1091-6490

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid beta protein (Abeta1-42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3beta (GSK-3beta). Deletion studies show that both tau and GSK-3beta bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3beta into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3beta. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3beta with mutant PS1 leads to increased phosphorylation of tau.