Maintained activity of glycogen synthase kinase-3beta despite of its phosphorylation at serine-9 in okadaic acid-induced neurodegenerative model.
Glycogen synthase kinase-3beta (GSK3beta) is recognized as one of major kinases to phosphorylate tau in Alzheimer's disease (AD), thus lots of AD drug discoveries target GSK3beta. However, the inactive form of GSK3beta which is phosphorylated at serine-9 is increased in AD brains. This is also inconsistent with phosphorylation status of other GSK3beta substrates, such as beta-catenin and collapsin response mediator protein-2 (CRMP2) since their phosphorylation is all increased in AD brains. Thus, we addressed this paradoxical condition of AD in rat neurons treated with okadaic acid (OA) which inhibits protein phosphatase-2A (PP2A) and induces tau hyperphosphorylation and cell death. Interestingly, OA also induces phosphorylation of GSK3beta at serine-9 and other substrates including tau, beta-catenin and CRMP2 like in AD brains. In this context, we observed that GSK3beta inhibitors such as lithium chloride and 6-bromoindirubin-3'-monoxime (6-BIO) reversed those phosphorylation events and protected neurons. These data suggest that GSK3beta may still have its kinase activity despite increase of its phosphorylation at serine-9 in AD brains at least in PP2A-compromised conditions and that GSK3beta inhibitors could be a valuable drug candidate in AD.
Lim
Yong-Whan
YW
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yoon
Seung-Yong
SY
Choi
Jung-Eun
JE
Kim
Sang-Min
SM
Lee
Hui-Sun
HS
Choe
Han
H
Lee
Seung-Chul
SC
Kim
Dong-Hou
DH
D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000201:enzymology*; D019319:Okadaic Acid / Q000633:toxicity; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D051381:Rats; D012694:Serine / Q000235:genetics / Q000378:metabolism
C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D019319:Okadaic Acid; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D018021:Lithium Chloride