DYRK1A was first described in the fruit fly Drosophila as the mini-brain mutation. The enzyme has been shown to be an important brain development factor. Its abnormal expression is thought to play a role in aberrant brain development, lifelong structural and functional neurological abnormalities, neural degeneration and neuronal death (Weigel et al 2011). In the case of individuals with DS, the 1.5x overexpression caused by Trisomy 21 results in retardation and moderate to severe cognitive impairment. DYRK1A is known to be involved at multiple sites of Alzheimer’s disease pathology in DS (Wiseman et al 2015); indeed most DS patients show early onset of AD. It also well established as playing a central role in a wide range of events that cause AD and so could be a key molecule bridging β-amyloid production and tau phosphorylation in AD (Weigel et al 2011, Ryoo et al 2007). The inhibition of DYRK1A therefore, offers a novel therapeutic approach for the treatment of AD and improving cognitive deficits in children affected by DS.
The loss of pancreatic β-cell mass is a central feature of both type 1 and type 2 diabetes, making it important, therefore, to understand the mechanisms involved in increasing β-cell mass. Pancreatic β-cells and neuronal cells share many similarities in terms of gene expression and development. Patients with DS have a greater than fourfold increase in the prevalence of type 1 diabetes leading to speculation into the possible role of DYRK1A in the regulation of β-cell proliferation. Research in both mice and human islet cells in vivo models show that DYRK1A is expressed in pancreatic islets and confirm that DYRK1A inhibition leads to β-cell proliferation and modulates glycaemia with normalised blood glucose at resting baseline and after a challenge to glucose (Rachdi et al 2014, Shen et al 2015, Wang et al 2015, Rachdi et al 2016, Dirice et al 2016). These studies show the crucial role of the DYRK1A pathway in the regulation of β-cell mass and carbohydrate metabolism and offer considerable promise for diabetes treatment.
Cancer cells present a unique set of signalling cascades and further investigations are required to fully understand whether DYRK1A plays a similar role in these. However, emerging studies in cancer models suggest DYRK1A could be a promising therapeutic target.