1. Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus.
- Author
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Granno S, Nixon-Abell J, Berwick DC, Tosh J, Heaton G, Almudimeegh S, Nagda Z, Rain JC, Zanda M, Plagnol V, Tybulewicz VLJ, Cleverley K, Wiseman FK, Fisher EMC, and Harvey K
- 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
- 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.
- Published
- 2019
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