| Abstrakt: |
Down syndrome (DS), caused by a genomic imbalance of human chromosome 21 (HSA21), is mainly observed as trisomy 21 and is the major genetic cause of mental retardation (MR). MR and associated neurological and behavioural alterations result from dysregulation in critical HSA21 genes and associated molecular pathways. Gene expression, transcriptome, proteome and functional genomics studies, in human, trisomic and transgenic mouse models have shown similar genotype/phenotype correlation and parallel outcomes suggesting that the same evolutionarily conserved genetic programmes are perturbed by gene-dosage effects. The expression variations caused by this gene-dosage imbalance may firstly induce brain functional variations at cellular level, as primary phenotypes, and finally induce neuromorphological alterations and cognitive deficits as secondary phenotypes. The identification of trisomic genes overexpressed in the brain and their function, their developmental regulated expression and their downstream effects, their interaction with other proteins, and their involvement in regulatory and metabolic pathways is giving a clearer view of the origin of the MR in DS. This led to the identification of potential targets in the altered molecular pathways involved in MR pathogenesis, such as calcineurin, NFATs and MAPK pathways, that may be potentially corrected, in the perspective of new therapeutic approaches. Treatment of DS mouse models with NMDA receptor or GABAA antagonists allowed post-drug rescue of cognitive deficits. Besides these new pharmacotherapies, the regulation of gene expression by microRNAs or small interfering RNAs provide exciting possibilities for exogenous correction of the aberrant gene expression in DS and provide potential directions for clinical therapeutics of MR. Herein, we highlight the genetic networks and molecular mechanisms implicated in the pathogenesis of MR in DS and, thereafter, we outline some of the therapeutic strategies for the treatment of this as yet incurable cognitive disorder with a considerable impact on public health. [ABSTRACT FROM AUTHOR] |
