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Sci Rep. 2019 May 13;9(1):7322. doi: 10.1038/s41598-019-43820-4.

Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus.

Author information

1
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
2
Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
3
Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA.
4
School of Health, Life and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK6 7AA, UK.
5
Hybrigenics Services - Fondation Jérôme Lejeune, 3-5 Impasse Reille, 75014, Paris, France.
6
UCL Genetics Institute, Darwin Building, Gower Street, London, WC1E 6BT, UK.
7
The Francis Crick Institute, 1 Midland Rd, Kings Cross, London, NW1 1AT, UK.
8
Department of Medicine, Imperial College, London, W12 0NN, UK.
9
London Down Syndrome Consortium (LonDownS), London, UK.
10
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK. kirsten.harvey@ucl.ac.uk.

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.

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