Abstract
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.
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Abbreviations
- AChEI:
-
Acetylcholinesterase inhibitor
- AD:
-
Alzheimer’s disease
- APP:
-
Amyloid precursor protein
- ATP:
-
Adenosine triphosphate
- BAC:
-
Bacterial artificial chromosome
- BFCN:
-
Basal forebrain cholinergic neurons
- CA1:
-
Cornu ammonis 1
- CA3:
-
Cornu ammonis 3
- CaMKII:
-
Calcium/calmodulin-dependent protein kinase
- CBR1:
-
Carbonyl reductase 1
- ChAT:
-
Choline acetyl transferase
- CIT-K:
-
Citron kinase
- CREB:
-
c-AMP response element-binding protein
- DS:
-
Down syndrome
- DSCAM:
-
Down syndrome cell adhesion molecule
- DSCR:
-
Down syndrome critical region
- DSCR1:
-
Down syndrome critical region gene 1
- DYN1:
-
Dynamin 1
- DYRK1A:
-
Dual-specificity tyrosine-(Y)-phosphorylation kinase 1A
- EGF:
-
Epidermal growth factor
- EPSCs:
-
Excitatory postsynaptic currents
- ERG:
-
Ets related gene
- ES:
-
Embryonic stem cells
- ETS2:
-
v-ets erythroblastosis virus E26 oncogene homolog 2
- GABAA :
-
Gamma-aminobutyric acid type A receptor
- GIRK2:
-
G-protein coupled inward rectifying potassium channel subunit 2
- HSA21:
-
Human chromosome 21
- IQ:
-
Intelligence quotient
- ITSN1:
-
Intersectin gene 1
- KCNJ6:
-
Potassium inwardly rectifying channel J6
- LPS:
-
Lipopolysaccharide
- LTD:
-
Long-term depression
- LTP:
-
Long-term potentiation
- MAPK:
-
Mitogen activated protein kinase
- MCIP1:
-
Myocyte-enriched calcineurin-interacting protein 1
- miRNA:
-
MicroRNA
- MMU16:
-
Mouse chromosome 16
- MR:
-
Mental retardation
- NFATc:
-
Nuclear factor of activated T cells
- NGF:
-
Nerve growth factor
- NMDA:
-
N-methyl-d-aspartate
- NMDA-R:
-
N-methyl-d-aspartate receptor
- PP1:
-
Protein phosphatase 1
- PTZ:
-
Pentylenetetrazol
- qRT-PCR:
-
Quantitative reverse transcriptase polymerase chain reaction
- RCAN1:
-
Regulator of calcineurin 1 protein
- S100B:
-
S100 calcium-binding protein beta
- SAGE:
-
Serial analysis of gene expression
- SHH:
-
Sonic hedgehog
- SIM2:
-
Single minded 2
- SNP:
-
Single nucleotide polymorphism
- SOD1:
-
Superoxide dismutase 1
- SYNJ1:
-
Synaptojanin gene 1
- TBS:
-
Theta-burst stimulation
- TPRD:
-
Tetratricopeptide repeat domain Down syndrome
- TTC3:
-
Tetratricopeptide repeat domain 3
- YAC:
-
Yeast artificial chromosome
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Acknowledgments
We are grateful to J. M. Delabar (University Paris 7) for his continuous support. We thank our colleagues of the Department of Molecular Biology-Jacques Monod at the Pateur Insitute (Paris) for their advice and support. We also thank L. Peltzer (University of French Polynesia) and C. Tetaria (Hospital Centre of French Polynesia) for their continuous support.
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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. In: Clelland, J. (eds) Genomics, Proteomics, and the Nervous System. Advances in Neurobiology, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7197-5_2
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