Molecular basis of pharmacotherapies for cognition in Down syndrome

Abstract

Intellectual disability (ID) in Down syndrome (DS) ranges from low normal to severely impaired, and has a significant impact on the quality of life of the individuals affected and their families. Because the incidence of DS remains at approximately one in 700 live births and the life span is now >50 years, development of pharmacotherapies for cognitive deficits is an important goal. DS is due to an extra copy of human chromosome 21 and has often been considered too complex a genetic abnormality to be amenable to intervention. However, recent successes in rescuing learning/memory impairments in a mouse model of DS suggest that this negative outlook may not be justified. In this article, we first review the DS phenotype, chromosome 21 gene content and mouse models, and then discuss recent successes and remaining challenges in the identification of targets for and preclinical evaluation of potential therapeutics.

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

“…It must be noted, however, that the interpretation of drug effects is often difficult in model animals of contiguous genetic syndromes such as DS. Because of the complex interactions between the human chromosome 21 genes, manipulation of a gene activity may affect the activities of other genes and lead to an unpredicted outcome 48 . Such an effect may also occur in the case of Dyrk1A.…”

Down Syndrome: A Complex and Interactive Genetic Disorder

“…Functional analyses of genetic information for DS have the potential to revolutionize our understanding about the gene-phenotype relationships in DS (Ait Yahya-Graison et al, 2007;Gardiner, 2010). Our meta-analysis of current functional analyses has indicated that cell cycling, maintenance, function, and adhesion, as well as DNA and RNA metabolism and binding and mitochondrial function are leading common mechanisms underlying DS phenotypes.…”

Avances Citogenéticos y Neurobiológicos en el Síndrome de Down

“…In particular, it has been found that overexpression of SOD1, DYRKLA, SIM2, C21orf5 and S100β genes influence the onset of both neuroanatomical and behavioral features similar to those presented by people with DS (Gardiner, 2009;Salehi et al, 2006). Specifically, it has been found a relationship between the overexpression of these genes and the emergence of alterations in brain plasticity, in the neuronal branches extension and cerebral apoptosis processes.…”

“…To date, the genes that have been overexpressed in mice to understand their contribution are APP, CBS, DSCR-1, DYRKLA, S100β, SIM2, C21orf5 and SOD1 (Gardiner, 2009;Rachidi & Lopes, 2008;Salehi et al, 2007).…”

“…Although the findings of these animal models are still scarce and its practical application is still limited, it may be considered that, in addition to providing basic information about the underlying etiology to DS, it is possible that their study also provide information, which on its basis early pharmacological interventions could be developed that prevent or compensate the appearance of some of the neuropsychological manifestations of DS (Gardiner, 2009;Rueda et al, 2012;Scorza andCavalheiro, 2011, Liu et al, 2011;Vacano et al, 2012) .…”