Downregulated Wnt/\u03b2-catenin signalling in the Down syndrome hippocampus

Simone Granno,Vincent Plagnol,Jonathon Nixon-Abell,Frances K Wiseman,Victor L J Tybulewicz,Kirsten Harvey,Elizabeth M C Fisher,Manuela Zanda,George Heaton,Zenisha Nagda,Justin Tosh,Jean-Christophe Rain,Karen Cleverley,Daniel C Berwick,Sultan Almudimeegh

doi:10.1038/s41598-019-43820-4

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.

Highlights

Down syndrome (DS) is the most common human aneuploidy, occurring in approximately 1/700–1000 live births[1]
We identified a significant increase in total GSK3β levels (Fig. 5F, red) along with reduced phosphorylation of the inhibitory Ser 9 residue in accordance with decreased canonical Wnt signaling activity
It is interesting that DKK3, which we found to be altered in the DS hippocampus, interacts with DYRK1A via its nuclear speckle-localising sequence[59]

Summary

Introduction

Down syndrome (DS) is the most common human aneuploidy, occurring in approximately 1/700–1000 live births[1]. We identified substantial Wnt signalling downregulation in the hippocampus of DS individuals with AD pathology and the Tc1 mouse model of DS This suggests the presence of a novel functional relationship between DS and Wnt signalling, which may contribute to the development of AD in the ageing DS population. Www.nature.com/scientificreports might arise from increased expression of key Hsa21-encoded proteins such as DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A). In support of this hypothesis, we present evidence of novel bimodal regulatory effects of DYRK1A overexpression, kinase inhibition and interaction with other Wnt signalling components. DYRK1A is thought to be an essential mediator of intellectual disability in DS, and has been proposed to contribute to DS/AD pathogenesis as well as idiopathic AD37–45

Results

Discussion

Conclusion