Inhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of beta-catenin phosphorylation.
Mutations in the presenilin 1 (PS1) gene are the most common genetic factor underlying the development of early onset familial Alzheimer's disease (FAD). Accumulating evidence has shown that FAD-linked mutations of PS1 enhance the generation of amyloid-beta (1-42) protein. Recently, beta-catenin has been shown to interact with PS1. beta-catenin is essential for the Wnt signalling pathway. However, the biological significance of the interaction between beta-catenin and PS1 in this signalling pathway remains to be clarified. In this study, we investigated the effect of FAD-linked PS1 (M146L) mutation in the Wnt signalling pathway using the conditioned medium containing Wnt-3A. The expression of mutated PS1 inhibited the Wnt-3A-induced accumulation of beta-catenin. Chase analysis of beta-catenin in Wnt-3A-stimulated cells following cycloheximide treatment revealed that PS1 mutation enhanced the generation of the higher molecular mass form of beta-catenin, most likely, ubiquitinated beta-catenin. In addition, the expression of mutated PS1 elevated the level of phosphorylated beta-catenin, which is targeted to the ubiquitin/proteasome pathway. Thus, it appears that PS1 (M146L) mutation down-regulates the Wnt-3A-induced accumulation of beta-catenin due to an increase in the level of phosphorylated beta-catenin.
Kawamura
Y
Y
Department of Dementia Research, National Insititute for Longevity Sciences, Obu, Aichi, Japan.
Kikuchi
A
A
Takada
R
R
Takada
S
S
Sudoh
S
S
Shibamoto
S
S
Yanagisawa
K
K
Komano
H
H
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D053764:Presenilin-1; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D053764:Presenilin-1; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin; C067713:lactacystin; D003513:Cycloheximide; D000111:Acetylcysteine