Down syndrome (DS), caused by a genomic imbalance of human chromosome 21(HSA21), is mainly observed as trisomy 21 and is the major genetic causeof mental retardation (MR). MR and associated neurological andbehavioural alterations result from dysregulation in critical HSA21genes and associated molecular pathways. Gene expression, transcriptome,proteome and functional genomics studies, in human, trisomic andtransgenic mouse models have shown similar genotype/phenotypecorrelation and parallel outcomes suggesting that the sameevolutionarily conserved genetic programmes are perturbed by gene-dosageeffects. The expression variations caused by this gene-dosage imbalancemay firstly induce brain functional variations at cellular level, asprimary phenotypes, and finally induce neuromorphological alterationsand cognitive deficits as secondary phenotypes. The identification oftrisomic genes overexpressed in the brain and their function, theirdevelopmental regulated expression and their downstream effects, theirinteraction with other proteins, and their involvement in regulatory andmetabolic pathways is giving a clearer view of the origin of the MR inDS. This led to the identification of potential targets in the alteredmolecular pathways involved in MR pathogenesis, such as calcineurin,NFATs and MAPK pathways, that may be potentially corrected, in theperspective of new therapeutic approaches. Treatment of DS mouse modelswith NMDA receptor or GABA(A) antagonists allowed post-drug rescue ofcognitive deficits. Besides these new pharmacotherapies, the regulationof gene expression by microRNAs or small interfering RNAs provideexciting possibilities for exogenous correction of the aberrant geneexpression in DS and provide potential directions for clinicaltherapeutics of MR. Herein, we highlight the genetic networks andmolecular mechanisms implicated in the pathogenesis of MR in DS and,thereafter, we outline some of the therapeutic strategies for thetreatment of this as yet incurable cognitive disorder with aconsiderable impact on public health.
CITATION STYLE
Rachidi, M., & Lopes, C. (2011). Mental Retardation and Human Chromosome 21 Gene Overdosage: From Functional Genomics and Molecular Mechanisms Towards Prevention and Treatment of the Neuropathogenesis of Down Syndrome (pp. 21–86). https://doi.org/10.1007/978-1-4419-7197-5_2
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