Deterioration of the transcriptional, splicing and elongation machinery inbrain of fetal Down Syndrome

Perturbation of brain development i.e. regulation of gene expression, diffe rentiation, growth and migration in Down Syndrome (DS) has been reported to occur early in life pointing to impairment of the complex system of transc ription and or translation and indeed, altered expression of transcription factors has been reported in adult DS brain. We therefore decided to compar e the transcriptional and translational machinery in cortex of brains of co ntrols and fetuses with Down syndrome in the second trimenon of gestation. We determined a series of transcription/translation factors by 2 D-electrop horesis followed by MALDI - identification and quantification with specific software. The protooncogene C-CRK, CRK-like protein, elongation factor 1-alpha 1, elo ngation factor 2. elongation factor tu and two out of four spots representi ng PTB-associated splicing factor PSF were significantly downregulated in b rain of fetal DS fetuses as compared to controls. The finding of reduced transcription and translation factors may indicate d eranged protein synthesis. The underlying cause for individual reduced tran scription., splicing and translation factors may be explained by chromosoma l 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.