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Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus.
- Source :
-
Scientific reports [Sci Rep] 2019 May 13; Vol. 9 (1), pp. 7322. Date of Electronic Publication: 2019 May 13. - Publication Year :
- 2019
-
Abstract
- Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer's disease and the 'Tc1' DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer's disease treatment.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Aged
Animals
Axin Protein metabolism
Catechin analogs & derivatives
Catechin pharmacology
Chromosomes, Human, Pair 21 genetics
Disease Models, Animal
Down Syndrome genetics
Down-Regulation drug effects
Female
HEK293 Cells
HeLa Cells
Humans
Male
Mice
Middle Aged
Protein Serine-Threonine Kinases genetics
Protein-Tyrosine Kinases genetics
RNA-Seq
Wnt Signaling Pathway drug effects
Dyrk Kinases
Alzheimer Disease pathology
Down Syndrome pathology
Hippocampus pathology
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
Wnt Signaling Pathway genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31086297
- Full Text :
- https://doi.org/10.1038/s41598-019-43820-4