Abstract
Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.
Highlights
IntroductionDown syndrome (DS), first described by J
Thierry BessonDown syndrome (DS), first described by J
DYRK1A is highly expressed in the brain [6,7] where it plays an important role in the adult central nervous system manifested by the diverse learning and memory deficits observed in DYRK1A transgenic mice [8]
Summary
Down syndrome (DS), first described by J. Encodes a dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A This enzyme appears to play a role during brain development by regulating neurogenesis and neuronal differentiation in mice [6]. DYRK1A is highly expressed in the brain [6,7] where it plays an important role in the adult central nervous system manifested by the diverse learning and memory deficits observed in DYRK1A transgenic mice [8]. Mice overexpressing DYRK1A show severe impairment in spatial learning and memory indicating alterations in both hippocampal and prefrontal cortical function [12], effects similar to those found in murine models of DS. (MMU16) and the human chromosome 21 (HSA21) [16] This shared synteny is the basis for mouse models of DS, such as the well-studied Ts65Dn [17] and the Ts1Cje [18] mice. By using the DYRK1A PST-001 inhibitor in Ts65Dn mice, learning and memory deficits in a contextual discrimination task seen in these animals can be rescued
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