| Summary: | Down syndrome (DS) is the most common human aneuploidy. It results from the presence of three copies, or trisomy, of human chromosome 21 (Hsa21). DS is associated with a plethora of characteristic clinical features, most notably learning disability, altered body morphology, congenital heart disease and early-onset Alzheimer’s disease (AD-DS). Despite knowledge of its primary cause, pathological mechanisms underlying DS are poorly understood, including potential deficits in essential signalling processes. This thesis investigates Wnt/β-catenin signalling dysfunction in DS. The Wnt signalling pathway is a fundamental transduction cascade with key roles in development, cancer and neurodegeneration. Particularly, mounting evidence suggests that AD neuropathology may be underscored by critical dysfunction of canonical Wnt signalling. Given the close relationship between AD and DS, it is proposed in this thesis that Wnt abnormalities may also be present in the DS brain. This hypothesis is thus investigated, combining bioinformatics with RNA and protein analysis in DS mouse models and humans. The evidence gathered here suggests canonical Wnt signalling is dysfunctional in the DS brain. Most importantly, Wnt signalling activity is suppressed in the adult DS hippocampus. Furthermore, this thesis identifies the Hsa21-encoded kinase DYRK1A, an essential contributor to DS, as a novel, bimodal Wnt signalling regulator. DYRK1A may both suppress and enhance Wnt activity, depending on the activation state of the pathway. It is proposed that, in DS, dosage imbalance of DYRK1A may substantially affects Wnt signalling, with a complex array of resulting transcriptional changes to Wnt target genes. This mechanism may contribute to several developmental and adult features of DS, particularly learning disability and AD-DS. Overall, these findings may provide key evidence for the global understanding of this condition, and targeting Wnt signalling may open unexplored avenues for therapeutic development.
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