Recent insights into the function of DYRK1A (2010)

The minibrain (mnb) gene of Drosophila encodes an evolutionarily conserved protein kinase that plays a significant role during postembryonic neurogenesis through the regulation of neural proliferation and neurogenesis. The orthologous kinase in mammals, DYRK1A, is the prototypic member of a subfamily of protein kinases [dual-specificity tyrosine (Y) phosphorylation-regulated kinase, DYRK] that autophosphorylate an essential tyrosine in the activation loop and phosphorylate their substrates on serine or threonine residues. Multiple studies in chicken, mice and humans provide evidence that DYRK1A also has an important function in vertebrate brain development. Given the localization of the human DYRK1A gene within the so-called Down syndrome critical region on chromosome 21, overexpression of DYRK1A due to the extra gene copy in trisomy 21 has been proposed to contribute to the neurodevelopmental alterations associated with Down syndrome. In addition, the discovery that microtubule-associated protein tau is phosphorylated by DYRK1A has implicated DYRK1A in the early onset neurofibrillary degeneration in Down syndrome. The hypothesis of a pathogenetic role of enhanced activity of DYRK1A in both neurodevelopment and neurodegeneration makes it a potentially intriguing target for therapeutic intervention. This minireview series summarizes recent advances in analysing the role of DYRK1A in neurogenesis and neurodegeneration and current knowledge about the regulation and the pharmacological inhibition of DYRK1A by small molecule drugs. Bringing together these diverse aspects of the function of DYRK1A in neuronal development and pathologies with the molecular mechanisms that control its activity should be helpful in appraising the potential of this important protein as a possible drug target. The minireview by Tejedor and Hämmerle deals with the roles of MNB and DYRK1A in neuronal development. Combined evidence obtained in Drosophila, chicken and mouse has revealed that this highly conserved kinase has several key roles in the transition from progenitor proliferation to neuronal differentiation and in the formation of neurites. The possible implication for the neurodevelopmental phenotype associated with Down syndrome is discussed. Although multiple proteins have already been proposed as substrates or interacting proteins related to neuronal functions of MNB/DYRK1A, it is of key importance to further dissect the molecular mechanisms of MNB/DYRK1A function in neurodevelopment. Wegiel, Gong and Hwang review the rapidly accumulating evidence from in vitro studies, animal models and postmortem biochemical and immunocytochemical studies of human brain for a role of DYRK1A in neurodegenerative diseases. Results from their own laboratories as well as from other groups show that DYRK1A overexpression in Down syndrome brains may contribute to Alzheimer’s-like neurodegeneration directly through hyperphosphorylation of tau as well as by affecting alternative splicing of tau pre-mRNA. In addition to tauopathy, DYRK1A may also play a role in amyloidosis and neurodegenerative diseases involving synucleinopathy. The proposed role of DYRK1A in Down syndrome and Down syndrome-associated neurodegeneration implies that rather small changes in expression level, and thus activity, severely affect the biological function of this protein kinase. The minireview by Becker and Sippl discusses the unusual autoactivation mechanisms of DYRK1A in relation to other kinases with a tyrosine in the activation loop and also deals with the other mechanisms by which the activity of DYRK1A may be controlled. In addition, they survey the small molecule inhibitors currently available to target DYRK1A and evaluate their potential application and limitations.