Integrative multi-omics analysis reveals conserved cell-projection deficits in human Down syndrome brains [TotalRNAseq]

Down syndrome (DS) is the most common genetic cause of cognitive disability. However, it is largely unclear how the triplication of a small gene subset may impinge on diverse aspects of DS brain physio-pathology. Here, we took a multi-omics approach and simultaneously analyze by RNA-seq and proteomics the expression signature of two diverse regions of human postmortem DS brains. We found that the overexpression of triplicated genes triggered global expression dysregulations differentially affecting transcripts, miRNA and proteins involved in both known and novel candidate pathways. Among the latter, we observed alteration of RNA splicing in DS brains specifically altering the expression of genes involved in cytoskeleton and axonal dynamics. Accordingly, we found alteration in axonal polarization in neurons from both DS human induced-pluripotent-stem cells and mice. Thus, our study provides an integrated multi-layer expression database capable of identifying new potential targets to possibly aid design future clinical interventions in DS.