Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in XXXX Down syndrome brains.

@entity1 @entity10015 @entity73 @entity46459 @entity19 @entity10075 @entity8251 @entity10366 @entity4297 @entity38112 @entity5498 @entity6998 @entity31586
Down syndrome (DS), or Trisomy 21, is the most common genetic cause of @entity73 and @entity4297 in the @entity1 population. Bioinformatic annotation has established that @entity1 chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: @entity31586 , @entity10075 , @entity46459 , @entity10015 , and @entity38112 . Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3'-untranslated region reporter assays, and gain- and loss-of-function experiments that @entity10015 and -802 can regulate the expression of the predicted mRNA target, the @entity5498 -CpG-binding protein ( @entity8251 ). We also demonstrate that @entity8251 is underexpressed in DS brain specimens isolated from either @entity1 or @entity19 . We further demonstrate that, as a consequence of attenuated @entity8251 expression, transcriptionally activated and silenced @entity8251 target genes, @entity10366 / @entity10366 and @entity6998 / @entity6998 , are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous @entity10015 or -802, by antagomir intra-ventricular injection, resulted in the normalization of @entity8251 and @entity8251 target gene expression. Taken together, these results suggest that improper repression of @entity8251 , secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.
