Prof. Dr. G. Lubec Department of Pediatrics University of Vienna Wahringer Giirte A-1090 Vienna, Austria

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2 Prof. Dr. G. Lubec Department of Pediatrics University of Vienna Wahringer Giirte A-1090 Vienna, Austria This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. Product Liability: The publisher can give no guarantee for all the information contained in this book. This does also refer to information about drug dosage and application thereof. In every individual case the respective user must check its accuracy by consulting other pharmaceuticalliterature. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use Springer-VerlaglWien Springer-Verlag Wien New York is a part of Springer Science+Business Media springeronline.com Typesetting: SNP Best-Set Typesetter Ltd., Hong Kong Printing: Holzhausen Druck & Medien GmbH, A-1140 Wien Printed on acid-free and chlorine-free bleached paper SPIN: CIP data applied for " With numerous (partly coloured) Figures ISSN ISBN -13: e-isbn -13 : DOl: /

3 G. Lubec (ed.) Advances in Down Syndrome Research Journal of Neural Transmission Supplement 67 SpringerWienN ew York

4 Preface In this publication information on biology, clinics and morphology of the Down Syndrome (DS) phenotype and mouse models thereof is provided in one volume in order to show the necessity of a common approach to solve the enigma, DS. And indeed, the DS phenotype may be seen as the consequence of a series of biochemical phenomena with aberrant RNA or protein expression of pivotal structures as e.g. transcription factors BACHI or ERG, with different expression patterns in fetal and adult DS.1t is also these structures that may be leading to the development of Alzheimer's disease neuropathology, inevitably supervening in adult DS, making studying DS a useful approach to investigate Alzheimer's disease. We learn that in early fetal life neuropathology does not show a specific histopathological pattern and we understand that molecular changes are preceding morphological alterations. The report of a new animal model forms the basis along with the already existing ones, to carry out biochemical and pharmacological experiments enabling testing current hypotheses, comparison with the human system and much more. Aberrant folate metabolism in mothers is a risk factor for developing DS and there is now biochemical evidence for impaired folate handling structures in fetal DS brain. Last not least overexpression of SOD-I, proposed to lead to the generation of reactive oxygen species and possibly responsible for neuronal loss is back to stage and the antioxidant system still is a matter of discussion, although literature indicates involvement of this pathway from early life. Many pathways, channels, metabolic, signaling, chaperone, cytoskeleton, etc.etc. are involved in the pathomechanisms leading to the DS phenotype and each may well explain impaired function or neuronal death, but the etiological question is still open and many findings may only reflect byphenomena or consequences of deranged different systems. There are also no definitive therapeutical targets so far and even existing tentative pharmacological targets have not been tested in humans due to restrictions by law or Ethical Committees or by cutting budgets for science or maybe even by (experimental) therapeutic nihilism. The editor of this (now third) booklet on DS is highly indebted to the Red Bull Company, Salzburg, Austria for generous support for many years and to the many partners worldwide that cooperated at different levels from providing antibodies to carrying out analyses or fruitful discussions. This is also to thank contributors to this volume as well as parents and patients who participated in studies published herein. Vienna, November 2003 G. Lubec

5 This book is dedicated to Dietrich Mateschitz, Salzburg, Austria

6 Contents Kazuki, Y., Schulz, T. C., Shinohara, T., Kadota, M., Nishigaki, R., Inoue, T., Kimura, M., Kai, Y., Abe, S., Shirayoshi, Y., Oshimura, M.: A new mouse model for Down syndrome Gardiner, K.: Predicting pathway perturbations in Down syndrome Shim, K. S., Ferrando-Miguel, R., Lubec, G.: Aberrant protein expression of transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with Down syndrome and Alzheimer's disease Rosner, M., Kowalska, A., Freilinger, A., Prusa, A-R., Marton, E., Hengstschlager, M.: Cell cycle and cell size regulation in Down Syndrome cells Sohn, S. Y., Weitzdoerfer, R., Mori, N., Lubec, G.: Transcription factor REST dependent proteins are comparable between Down Syndrome and control brains: challenging a hypothesis de Haan, J. B., Susil, B., Pritchard, M., Kola, I.: An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the "gene dosage effect" hypothesis Fountoulakis, M., Gulesserian, T., Lubec, G.: Overexpression of C 1-tetrahydrofolate synthase in fetal Down Syndrome brain Lubec, G., Bajo, M., Cheon, M. S., Bajova, H., Matherly, L. H.: Increased expression of human reduced folate carrier in fetal Down syndrome brain Thiery, E., Thomas, S., Vacher, S., Delezoide, A.-L., Delabar, J. M., Creau, N.: Chromosome 21 KlR channels in brain development Shim, K. S., Bergelson, J. M., Furuse, M., Ovod, V., Krude, T., Lubec, G.: Reduction of chromatin assembly factor 1 p60 and C21 orf2 protein, encoded on chromosome 21, in Down Syndrome brain Hammerle, B., Elizalde, C., Galceran, J., Becker, W., Tejedor, F. J.: The MNBIDYRKIA protein kinase: neurobiological functions and Down syndrome implications Galceran, J., de Graaf, K., Tejedor, F. J., Becker, W.: The MNBIDYRK1A protein kinase: genetic and biochemical properties Pollak, D., Cairns, N., Lubec, G.: Cytoskeleton derangement in brain of patients with Down Syndrome, Alzheimer's disease and Pick's disease Unterberger, U., Lubec, G., Dierssen, M., Stoltenburg-Didinger, G., Farreras, J. C., Budka, H.: The cerebral cortex in Fetal Down Syndrome Colas, D., London, J., Cespuglio, R., Sarda, N.: Polysomnography in transgenic hsodi mice as Down syndrome model Nicham, R., Weitzdorfer, R., Hauser, E., Freidl, M., Schubert, M., Wurst, E., Lubec, G., Seidl, R.: Spectrum of cognitive, behavioural and emotional problems in children and young adults with Down syndrome Ferrando-Miguel, R., Cheon, M. S., Yang, J.-W., Lubec, G.: Overexpression of transcription factor BACH1 in fetal Down Syndrome brain Shapiro, B. L.: Down syndrome and associated congenital malformations Lubec, G., Sohn, S. Y.: RNA Microarray analysis of channels and transporters in normal and fetal Down Syndrome (trisomy 21) brain

7 x Contents Cheon, M. S., Kim, S. H., Fountoulakis, M., Lubec, G.: Heart type fatty acid binding protein (H-FABP) is decreased in brains of patients with Down syndrome and Alzheimer's disease Prusa, A.-R., Marton, E., Rosner, M., Freilinger, A., Bernaschek, G., Hengstschlager, M.: Stem cell marker expression in human trisomy 21 amniotic fluid cells and trophoblasts Listed in Current Contents