Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1.

The most common genetic disorder Down syndrome (DS) displays various developmental defects including mental retardation, learning and memory deficit, the early onset of Alzheimer's disease (AD), congenital heart disease, and craniofacial abnormalities. Those characteristics result from the extra-genes located in the specific region called nDown syndrome critical region (DSCR)' in human chromosome 21. In this review, we summarized the recent findings of the DYRK1A and RCAN1 genes, which are located on DSCR and thought to be closely associated with the typical features of DS patients, and their implication to the pathogenesis of neural defects in DS. DYRK1A phosphorylates several transcriptional factors, such as CREB and NFAT, endocytic complex proteins, and AD-linked gene products. Meanwhile, RCAN1 is an endogenous inhibitor of calcineurin A, and its unbalanced activity is thought to cause major neuronal and/or non-neuronal malfunction in DS and AD. Interestingly, they both contribute to the learning and memory deficit, altered synaptic plasticity, impaired cell cycle regulation, and AD-like neuropathology in DS. By understanding their biochemical, functional and physiological roles, we hope to get important molecular basis of DS pathology, which would consequently lead to the basis to develop the possible therapeutic tools for the neural defects in DS. [BMB reports 2009; 42(1): 6-15].