Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis.
Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown. Here we show that presenilin-1 forms a complex with beta-catenin in vivo that increases beta-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize beta-catenin, and lead to increased degradation of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-beta protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer's disease.
Zhang
Z
Z
Department of Neurology, Harvard Medical School, The Children's Hospital, Boston, Massachusetts 02115, USA.
Hartmann
H
H
Do
V M
VM
Abramowski
D
D
Sturchler-Pierrat
C
C
Staufenbiel
M
M
Sommer
B
B
van de Wetering
M
M
Clevers
H
H
Saftig
P
P
De Strooper
B
B
He
X
X
Yankner
B A
BA
D025601:Adenomatous Polyposis Coli Protein; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D009474:Neurons / Q000473:pathology*; D053764:Presenilin-1; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D016229:Amyloid beta-Peptides; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D015534:Trans-Activators; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3