Presenilin 1 Associates with Glycogen Synthase Kinase-3β and Its Substrate Tau

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 16; pp. 9637 - 9641
• Main Authors: Takashima, Akihiko, Murayama, Miyuki, Murayama, Ohoshi, Kohno, Toshiyuki, Honda, Toshiyuki, Yasutake, Kaori, Nihonmatsu, Naomi, Mercken, Marc, Yamaguchi, Haruyasu, Sugihara, Shiro, Wolozin, Benjamin
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences of the United States of America 04.08.1998; National Acad Sciences; The National Academy of Sciences
• Subjects: Alzheimers disease; Antibodies; Biological Sciences; COS cells; Genetic mutation; Neurons; Neuroscience; Phosphorylation; Presenilins; Proteins; Reactivity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.16.9637

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 β protein (Aβ1-42). We now show that PS1 also regulates phosphorylation of the micro-tubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3β (GSK-3β ). Deletion studies show that both tau and GSK-3β 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-3β into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3β . Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3β and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3β with mutant PS1 leads to increased phosphorylation of tau.