A recent paper in Nature Medicine showed that Down syndrome brains have reduced expression of Sorting nexin 27 (SNX27) and CCAAT/enhancer binding protein beta (C/EBP beta) and identified C/EBP beta as a transcription factor for SNX27. Down syndrome results in overexpression of miR-155, a chromosome 21–encoded microRNA that negatively regulates C/EBP beta, thereby reducing SNX27 expression. SNX27 is a brain-enriched PDZ domain protein, that regulates endocytic sorting and trafficking. The authors found that Snx27 -/- mice have severe neuronal deficits in the hippocampus and cortex. Snx27 +/- mice show defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors). Besides demonstrating a role of SNX27 in synaptic function and Down syndrome molecular pathogenesis, the paper showed that upregulation of SNX27 in the hippocampus of Down syndrome mice rescues the synaptic and cognitive deficits and thus can have therapeutic relevance.
Posted by Nicola Brunetti-Pierri, MD