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4 - New perspectives on molecular and genic therapies in Down syndrome

Published online by Cambridge University Press:  05 July 2011

By
Jean-Maurice Delabar
Edited by
Jean-Adolphe Rondal ,
Juan Perera  and
Donna Spiker
Jean-Maurice Delabar
Affiliation:
University of Paris Diderot
Jean-Adolphe Rondal
Affiliation:
Université de Liège, Belgium
Juan Perera
Affiliation:
Universitat de les Illes Balears, Palma de Mallorca
Donna Spiker
Affiliation:
Stanford Research Institute International
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Summary

Down syndrome and phenotypes

Trisomy 21 exerts a powerful downward effect on intelligence quotient (IQ). In contrast to normally developing children, there is a progressive IQ decline in Down syndrome (DS) beginning in the first year of life. The ratio of mental age to chronological age is not constant. By adulthood, IQ is usually in the moderately to severely retarded level (IQ 25–55) with an upper limit on mental age of approximately 7–8 years although a few individuals have IQ in the lower normal range (70–80). The molecular basis and the genes involved in this early decline across development are not known. This low IQ corresponds to an overall mental retardation. The short-term memory development of individuals with DS has been the subject of considerable research. Recent observation of the development of encoding strategies through the ages of 5 to 8 years suggests that this is a complex process involving the maturation of attentional and inhibitory processes (Palmer, 2000). The alterations in the cognition processes have not yet been related to the neuropathological features of DS.

At a gross morphological level, DS brains are smaller than normal. A 15%–20% decrease is generally reported (Jernigan et al., 1993; Pinter et al., 2001). Three brain areas are mainly altered: prefrontal cortex, hippocampus, and cerebellum. Postmortem studies and noninvasive brain imaging have revealed reduced sizes of the brain hemispheres, brainstem, and cerebellum (Kesslak et al., 1994; Raz et al., 1995).

Type
Chapter
Information
Neurocognitive Rehabilitation of Down Syndrome
Early Years
 , pp. 52 - 70
Publisher: Cambridge University Press
Print publication year: 2011

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References

Adayev, T., Chen-Hwang, M. C., Murakami, N., Wang, R., Hwang, Y. W. (2006). MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins. Biochemical and Biophysical Research Communications, 351(4), 1060–1065.CrossRefGoogle ScholarPubMed
Ahn, K. J., Jeong, H. K., Choi, H. S., et al. (2006). DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiology of Disease, 22(3), 463–472.CrossRefGoogle ScholarPubMed
Aït Yahya-Graison, E., Aubert, J., Dauphinot, L., et al. (2007). Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. American Journal of Human Genetics, 81(3), 475–491.CrossRefGoogle ScholarPubMed
Arron, J. R., Winslow, M. M., Polleri, A., et al. (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, 441(7093), 595–600.CrossRefGoogle ScholarPubMed
Bain, J., McLauchlan, H., Elliott, M., Cohen, P. (2003). The specificities of protein kinase inhibitors: an update. Biochemical Journal, 371(1), 199–204.Google ScholarPubMed
Bales, K. R., Tzavara, E. T., Wu, S., et al. (2006). Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. Journal of Clinical Investigation, 116(3), 825–832.CrossRefGoogle Scholar
Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J., Reeves, R. H. (2000). Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Human Molecular Genetics, 9, 195–202.CrossRefGoogle ScholarPubMed
Becker, L. E., Mito, T., Takashima, S., Onodera, K. (1991). Growth and development of the brain in Down syndrome. In C. J. Epstein (ed.), The Morphogenesis of Down Syndrome, pp.133–152. New York: Wiley-Liss.Google ScholarPubMed
Belichenko, P. V., Masliah, E., Kleschevnikov, A. M., et al. (2005). Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome. Journal of Comparative Neurology, 480(3), 281–298.CrossRefGoogle Scholar
Branchi, I., Bichler, Z., Minghetti, L., et al. (2004). Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration. Journal of Neuropathology and Experimental Neurology, 63(5), 429–440.CrossRefGoogle ScholarPubMed
Chabert, C., Jamon, M., Cherfouh, A., et al. (2004). Functional analysis of genes implicated in Down syndrome: 1. Cognitive abilities in mice transpolygenic for Down Syndrome Chromosomal Region-1 (DCR-1). Behavior Genetics, 34(6), 559–569.CrossRefGoogle Scholar
Chen-Hwang, M. C., Chen, H. R., Elzinga, M., Hwang, Y. W. (2002). Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. Journal of Biological Chemistry, 277(20), 17597–17604.CrossRefGoogle ScholarPubMed
Clark, S., Schwalbe, J., Stasko, M. R., Yarowsky, P. J., Costa, A. C. (2006). Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Experimental Neurology, 200(1), 256–261.CrossRefGoogle ScholarPubMed
Costa, A. C., Scott-McKean, J. J., Stasko, M. R. (2008). Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology, 33(7), 1624–1632.CrossRefGoogle ScholarPubMed
Dahmane, N., Charron, G., Lopes, C., et al. (1995). Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. Proceedings of the National Academy of Sciences of the United States of America, 92(20), 9191–9195.CrossRefGoogle ScholarPubMed
Dauphinot, L., Lyle, R., Rivals, I., et al. (2005). The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. Human Molecular Genetics, 14(3), 373–384.CrossRefGoogle ScholarPubMed
Davisson, M. T., Schmidt, C., Akeson, E. C. (1990). Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Progress in Clinical and Biological Research, 360, 263–280.Google ScholarPubMed
Delabar, J. M., Theophile, D., Rahmani, Z., et al. (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. European Journal of Human Genetics, 1(2), 114–124.CrossRefGoogle ScholarPubMed
Fernandez, F., Morishita, W., Zuniga, E., et al. (2007). Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nature Neuroscience, 10(4), 411–413.CrossRefGoogle Scholar
Ferrer, I., Barrachina, M., Puig, B., et al. (2005). Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. Neurobiology of Disease, 20(2), 392–400.CrossRefGoogle ScholarPubMed
Franceschi, M., Comola, M., Piattoni, F., Gualandri, W., Canal, N. (1990). Prevalence of dementia in adult patients with trisomy 21. American Journal of Medical Genetics, Suppl. 7, 306–308.Google Scholar
Gardiner, K., Davisson, M. T., Crnic, L. S. (2004). Building protein interaction maps for Down syndrome. Briefings in Functional Genomics & Proteomics, 3(2), 142–156.CrossRefGoogle Scholar
Gitton, Y., Dahmane, N., Baik, S., et al. (2002). HSA21 expression map initiative. A gene expression map of human chromosome 21 orthologues in the mouse. Nature, 420 (6915), 586–590.CrossRefGoogle Scholar
Golden, J. A. and Hyman, B. T. (1994). Development of the superior temporal neocortex is anomalous in trisomy 21. Journal of Neuropathology and Experimental Neurology, 53, 513–520.CrossRefGoogle ScholarPubMed
Guedj, F., Sébrié, C., Rivals, I., et al. (2009). Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS ONE, 4(2), e4606.CrossRefGoogle ScholarPubMed
Guimera, J., Casas, C., Estivill, X., Pritchard, M. (1999). Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. Genomics, 57(3), 407–418.CrossRefGoogle ScholarPubMed
Hardy, J. & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297, 353–356.CrossRefGoogle ScholarPubMed
Hesser, B. A., Liang, X. H., Camenisch, G., et al. (2004). Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood, 104(1), 149–158.CrossRefGoogle Scholar
Himpel, S., Tegge, W., Frank, R., et al. (2000). Specificity determinants of substrate recognition by the protein kinase DYRK1A. Journal of Biological Chemistry, 275(4), 2431–2438.CrossRefGoogle ScholarPubMed
Holtzman, D. M., Santucci, D., Kilbridge, J., et al. (1996). Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proceedings of the National Academy of Sciences of the United States of America, 93, 13333–13338.CrossRefGoogle Scholar
Insausti, A. M., Megias, M., Crespo, D., et al. (1998). Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of Down syndrome. Neuroscience Letters, 253, 175–178.CrossRefGoogle ScholarPubMed
Jernigan, T. L. A., Sowell, E., Doherty, S., Hesselink, J. R. (1993). Cerebral morphologic distinctions between Williams and Down syndromes. Archives of Neurology, 50, 186–191.CrossRefGoogle ScholarPubMed
Kentrup, H., Becker, W., Heukelbach, J., et al. (1996). Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. Journal of Biological Chemistry, 271(7), 3488–3495.CrossRefGoogle ScholarPubMed
Kesslak, J. P., Nagata, S. F., Lott, I., Nalcioglu, O. (1994). Magnetic resonance imaging analysis of age-related changes in the brains of individuals with Down's syndrome. Neurology, 44, 1039–1045.CrossRefGoogle ScholarPubMed
Kleschevnikov, A. M., Belichenko, P. V., Villar, A. J., et al. (2004). Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. Journal of Neuroscience, 24 (37), 8153–8160.CrossRefGoogle ScholarPubMed
Korenberg, J. R., Aaltonen, J., Brahe, C., et al. (1997). Report and abstracts of the Sixth International Workshop on Human Chromosome 21 Mapping 1996. Cold Spring Harbor, New York, USA. May 6–8, 1996. Cytogenetics and Cell Genetics, 79(1–2), 21–52.Google ScholarPubMed
Lee, E. B., Leng, L. Z., Zhang, B., et al. (2006). Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. Journal of Biological Chemistry, 281(7), 4292–4299.CrossRefGoogle ScholarPubMed
Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S., Antonarakis, S. E. (2004). Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Research, 14(7), 1268–1274.CrossRefGoogle Scholar
Mann, D. M., Royston, M. C., Ravindra, C. R. (1990). Some morphometric observations on the brains of patients with Down's syndrome: their relationship to age and dementia. Journal of the Neurological Sciences 99, 153–164.CrossRefGoogle ScholarPubMed
Moran, T. H., Capone, G. T., Knipp, S., et al. (2002). The effects of piracetam on cognitive performance in a mouse model of Down's syndrome. Physiology & Behavior, 77(2–3), 403–409.CrossRefGoogle Scholar
O'Doherty, A., Ruf, S., Mulligan, C., et al. (2005). An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science, 309(5743), 2033–2037.CrossRefGoogle ScholarPubMed
Olson, L. E., Roper, R. J., Baxter, L. L., et al. (2004). Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Developmental Dynamics, 230(3), 581–589.CrossRefGoogle ScholarPubMed
Ortiz-Abalia, J., Sahún, I., Altafaj, X., et al. (2008). Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome. American Journal of Human Genetics, 83(4), 479–488.CrossRefGoogle ScholarPubMed
Palmer, S. (2000). Working memory: a developmental study of phonological recoding. Memory, 8, 179–193.CrossRefGoogle ScholarPubMed
Pellegrini-Calace, M. & Tramontano, A. (2006). Identification of a novel putative mitogen-activated kinase cascade on human chromosome 21 by computational approaches. Bioinformatics, 22(7), 775–778.CrossRefGoogle ScholarPubMed
Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T., Reiss, A. L. (2001). Neuroanatomy of Down's syndrome: a high-resolution MRI study. American Journal of Psychiatry, 158, 1659–1665.CrossRefGoogle ScholarPubMed
Rachidi, M., Lopes, C., Delezoide, A. L., Delabar, J. M. (2006). C21orf5, a human candidate gene for brain abnormalities and mental retardation in Down syndrome. Cytogenetic and Genome Research, 112(1–2), 16–22.CrossRefGoogle ScholarPubMed
Rahmani, Z., Lopes, C., Rachidi, M., Delabar, J. M. (1998). Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues. Biochemical and Biophysical Research Communications, 253(2), 514–518.CrossRefGoogle ScholarPubMed
Raz, N., Torres, I. J., Briggs, S. D., et al. (1995). Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry. Neurology, 45, 356–366.CrossRefGoogle ScholarPubMed
Reymond, A., Marigo, V., Yaylaoglu, M. B., et al. (2002). Human chromosome 21 gene expression atlas in the mouse. Nature, 420(6915), 582–586.CrossRefGoogle ScholarPubMed
Ronan, A., Fagan, K., Christie, L., et al. (2007). Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. Journal of Medical Genetics, 44(7), 448–451.CrossRefGoogle ScholarPubMed
Roper, R. J., Baxter, L. L., Saran, N. G., et al. (2006). Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice. Proceedings of the National Academy of Sciences of the United States of America, 103(5), 1452–1456.CrossRefGoogle Scholar
Roper, R. J., VanHorn, J. F., Cain, C. C., Reeves, R. H. (2009). A neural crest deficit in Down syndrome mice is associated with deficient mitotic response to Sonic hedgehog. Mechanisms of Development, 126(3–4), 212–219.CrossRefGoogle ScholarPubMed
Rueda, N., Flórez, J., Martínez-Cué, C. (2008). Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neuroscience Letters, 433(1), 22–27.CrossRefGoogle Scholar
Sago, H., Carlson, E. J., Smith, D. J., et al. (1998). Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proceedings of the National Academy of Sciences of the United States of America, 95, 6256–6261.CrossRefGoogle ScholarPubMed
Scholtzova, H., Wadghiri, Y. Z., Douadi, M., et al. (2008). Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging. Journal of Neuroscience Research, 86(12), 2784–2791.CrossRefGoogle ScholarPubMed
Schulz, E. & Scholz, B. (1992). [Neurohistological findings in the parietal cortex of children with chromosome aberrations.] Journal für Hirnforschung, 33(1), 37–62.Google ScholarPubMed
Sebrié, C., Chabert, C., Ledru, A., et al. (2008). In vivo MRI study of brain volumetric alterations in a transgenic YAC model of partial trisomy 21. Anatomical Record, 291(3), 254–262.CrossRefGoogle Scholar
Shinohara, T., Tomizuka, K., Miyabara, S., et al. (2001). Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome. Human Molecular Genetics, 10(11), 1163–1175.CrossRefGoogle ScholarPubMed
Siarey, R. J., Carlson, E. J., Epstein, C. J., et al. (1999). Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology, 38(12), 1917–1920.CrossRefGoogle ScholarPubMed
Siarey, R. J., Stoll, J., Rapoport, S. I., Galdzicki, Z. (1997). Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down Syndrome. Neuropharmacology, 36, 1549–1554.CrossRefGoogle Scholar
Smith, D. J., Stevens, M. E., Sudanagunta, S. P., et al. (1997). Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nature Genetics, 16(1), 28–36.CrossRefGoogle ScholarPubMed
Thomas, S., Thiery, E., Aflalo, R., et al. (2003). PCP4 is highly expressed in ectoderm and particularly in neuroectoderm derivatives during mouse embryogenesis. Gene Expression Patterns, 3(1), 93–97.CrossRefGoogle ScholarPubMed
Praag, H., Lucero, M. J., Yeo, G. W., et al. (2007). Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice. Journal of Neuroscience, 27(22): 5869–5878.CrossRefGoogle ScholarPubMed
White, N. S., Alkire, M. T., Haier, R. J. (2003). A voxel-based morphometric study of nondemented adults with Down Syndrome. NeuroImage, 20, 393–403.CrossRefGoogle ScholarPubMed
Woods, Y. L., Cohen, P., Becker, W., et al. (2001a). The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochemistry Journal, 355(3), 609–615.CrossRefGoogle ScholarPubMed
Woods, Y. L., Rena, G., Morrice, N., et al. (2001b). The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochemistry Journal, 355(3), 597–607.CrossRefGoogle ScholarPubMed
Xie, W., Ramakrishna, N., Wieraszko, A., Hwang, Y. W. (2008). Promotion of neuronal plasticity by (-)-epigallocatechin-3-gallate. Neurochemical Research, 33(5): 776–783.CrossRefGoogle ScholarPubMed

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