DYRK1A and cognition: A lifelong relationship

The dosage of the serine threonine kinase DYRK1A is critical in the central nervous system (CNS) during development and aging. This review analyzes the functions of this kinase by considering its interacting partners and pathways. The role of DYRK1A in controlling the differentiation of prenatal newly formed neurons is presented separately from its role at the pre- and post-synaptic levels in the adult CNS; its effects on synaptic plasticity are also discussed. Because this kinase is positioned at the crossroads of many important processes, genetic dosage errors in this protein produce devastating effects arising from DYRK1A deficiency, such as in MRD7, an autism spectrum disorder, or from DYRK1A excess, such as in Down syndrome. Effects of these errors have been shown in various animal models including Drosophila, zebrafish, and mice. Dysregulation of DYRK1A levels also occurs in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Finally, this review describes inhibitors that have been assessed in vivo. Accurate targeting of DYRK1A levels in the brain, with either inhibitors or activators, is a future research challenge.