DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome

Abstract

Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer’s disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

“…Furthermore, Dyrk1a appears to have a crucial role during central nervous system development (CNS), via its regulation of multiple targets in both the nucleus and the cytoplasm via phosphorylation [extensively reviewed in (Becker et al. ; Duchon and Herault )]. Normalization of Dyrk1a copy number in otherwise trisomic mouse models has resulted in some improvements in cognitive and behavioral phenotypes (Garcia‐Cerro et al.…”

“…Several recent reviews have discussed in detail the numerous targets of Dyrk1a , and have suggested how molecular mechanisms altered by excessive Dyrk1a could affect cognitive and behavioral processes (Wegiel et al. ; Park and Chung ; Duchon and Herault ; Antonarakis ). In addition, several reports have described potential Dyrk1a inhibitors and their possible use for correcting DS‐related deficits (de la Torre and Dierssen ; Becker et al.…”

“…In addition, several reports have described potential Dyrk1a inhibitors and their possible use for correcting DS‐related deficits (de la Torre and Dierssen ; Becker et al. ; Duchon and Herault ). The present review extends those recent analyses by emphasizing an additional but crucial aspect of the therapeutic potential of Dyrk1a inhbition for DS – the importance of understanding when and where Dyrk1a expression and activity is elevated and determining whether some periods of elevated Dyrk1a may represent sensitive periods of developmental vulnerability for establishing long‐lasting DS structural and functional phenotypes.…”

“…). Consequently, Dyrk1a has been identified as a target for therapeutic drug development in DS (de la Torre and Dierssen ; Duchon and Herault ). Less consideration has been given, however, to when and where the trisomic gene is overexpressed, and whether that spatiotemporal regulation is causally related to the developing phenotype.…”

Biological Consequences of Priming Phosphorylation in Cancer Development

“…In mouse, DYRK1A is essential for embryonic development, especially in the nervous systems, and unbalanced gene dosage causes developmental delay and abnormal brain morphology [68][69][70][71][72][73][74][75]. In neuronal progenitor cells, overexpression of DYRK1A bring to the attenuation of cell proliferation that promotes the switch to a quiescent state or differentiation.…”