Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis
| Autor: | Henrike Hartmann, Hans Clevers, Viet Minh Do, Bernd Sommer, Matthias Staufenbiel, Christine Sturchler-Pierrat, Paul Saftig, Zhuohua Zhang, Xi He, M. Van De Wetering, B. De Strooper, Dorothee Abramowski, Bruce A. Yankner |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Programmed cell death
Transgene Adenomatous Polyposis Coli Protein Golgi Apparatus Apoptosis Mice Transgenic Biology Endoplasmic Reticulum medicine.disease_cause Presenilin Cell Line Glycogen Synthase Kinase 3 Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease GSK-3 mental disorders Presenilin-1 medicine Animals Humans beta Catenin 030304 developmental biology Neurons 0303 health sciences Mutation Amyloid beta-Peptides Multidisciplinary Brain Membrane Proteins medicine.disease Rats nervous system diseases Cell biology Cytoskeletal Proteins Microscopy Fluorescence nervous system Catenin Calcium-Calmodulin-Dependent Protein Kinases Immunology Trans-Activators Alzheimer's disease Signal transduction 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Nature. 395:698-702 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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