Deterioration of the transcriptional, splicing and elongation machinery in brain of fetal Down Syndrome
Perturbation of brain development i.e. regulation of gene expression, differentiation, growth and migration in Down Syndrome (DS) has been reported to occur early in life pointing to impairment of the complex system of transcription and or translation and
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1 Department of Pediatrics, University of Vienna, Vienna, Austria Gene Technologies, eNS Research, F. Hoffmann La Roche, Basle, Switzerland 3Department of Neonatology, University of Vienna, Vienna, Austria
Summary. Perturbation of brain development i.e. regulation of gene expression, differentiation, growth and migration in Down Syndrome (DS) has been reported to occur early in life pointing to impairment of the complex system of transcription and or translation and indeed, altered expression of transcription factors has been reported in adult DS brain. We therefore decided to compare the transcriptional and translational machinery in cortex of brains of controls and fetuses with Down syndrome in the second trimenon of gestation. We determined a series of transcription/translation factors by 2 Delectrophoresis followed by MALDI - identification and quantification with specific software. The proto oncogene C-CRK, CRK-like protein, elongation factor I-alpha 1, elongation factor 2, elongation factor tu and two out of four spots representing PTB-associated splicing factor PSF were significantly downregulated in brain of fetal DS fetuses as compared to controls. The finding of reduced transcription and translation factors may indicate deranged protein synthesis. The underlying cause for individual reduced transcription, splicing and translation factors may be explained by chromosomal imbalance or by posttranslational modifications as e.g. phosphorylation, known to be aberrant in DS. Reduced expression of transcription factors in fetal DS during early life may be responsible or reflecting impaired brain development and deficient wiring of the brain in DS.
Introduction
Brain development and differentiated neuronal functions depend on coordinated patterns of gene activation and inactivation. 30%-50% of genes in mammals are specifically expressed in the nervous system. The differential expression of these genes in distinct spatial and temporal patterns is necessary for generating the vast variety of neuronal phenotypes. The interaction and regulation of the repertoire of transcription factors - in human nervous system 1,500-2,500 transcription factors exhibit specific expression - may
G. Lubec (ed.), Protein Expression in Down Syndrome Brain © Springer-Verlag/Wien 2001
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permit the precision and nuance of control of gene expression required for complex functional systems such as the nervous system. Transcriptional regulation may also be an important part of the machinery for higher functions of the nervous system such as learning or memory. A single short stimulus causes longlasting elevations in the synthesis of TH and other proteins in postsynaptic neurons, having been attributed to increased mRNA synthesis. From a variety of studies it is clear that de novo synthesis of mRNA and protein is required for learning and memory, therefore, an altered transcriptional state is associated with memory aquisition, just as it is associated with cellular differentiation. Thus subtle differences in the combin
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