Exp Neurobiol 2013; 22(4): 244-248
Published online December 30, 2013
© The Korean Society for Brain and Neural Sciences
Joongkyu Park1,2 and Kwang Chul Chung1*
1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea, 2Program in Cellular Neuroscience, Neurodegeneration and Repair (CNNR), Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA
Correspondence to: *To whom correspondence should be addressed.
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Down syndrome (DS) is one of the most common genetic disorders accompanying with mental retardation, cognitive impairment, and deficits in learning and memory. The brains with DS also display many neuropathological features including alteration in neurogenesis and synaptogenesis and early onset of Alzheimer's disease (AD)-like symptoms. Triplication of all or a part of human chromosome 21, especially the 21q22.1~21q22.3 region called 'Down syndrome critical region (DSCR)', has been considered as the main cause of DS. One gene product of DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been highlighted as a key contributor to the neural consequences of DS. This minireview summarizes accumulating recent reports about Dyrk1A involvement in the neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation, which is mainly focusing on Dyrk1A-mediated regulation of cytoskeletal proteins, such as tubulin, actin, and microtubule-associated protein tau. Understanding the molecular mechanisms of these phenomena may provide us a rational for new preventive and therapeutic treatment of DS.
Keywords: down syndrome, Dyrk1A, neuritogenesis, synaptogenesis, cytoskeletal proteins
Since Dr. John L. H. Down first described the patients with mental retardation and characteristic facial appearance , Down syndrome (DS) has been characterized as one of the most common genetic disorders with an incidence of 1 in every 700~800 live births. DS patients also display cognitive impairment, learning and memory deficit, a high risk of leukemia, congenital heart disease, and hypotonia [2-4]. The main cause of DS is trisomy of all or a part of human chromosome 21 [2, 5]. Several studies of the partial trisomy 21 patients characterized a region of human chromosome 21 [21q22.1~21q22.3; named as 'Down syndrome critical region (DSCR)'] as a key suspect of DS symptoms [6-8].
Among the 33 presumed genes in DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) has been intensively studied due to its close association with various cellular and neuronal processes . Dyrk1A is a proline-directed serine/threonine kinase  that phosphorylates more than 20 substrates involved in various cellular processes . More importantly, Dyrk1A up-regulation by trisomy 21 is implicated in the neural defects observed in the patients with DS .
Interestingly, accumulating data for recent years have suggested that Dyrk1A is involved in the regulation of cytoskeletal proteins such as tubulin, actin, and microtubule-associated protein tau and the alteration in neurogenesis of DS. In this context, this minireview focuses and discusses Dyrk1A and its link to neuropathologic features of DS.
The brains from DS patients have shown alteration in neurogenesis and synaptogenesis. The cortices from DS infant patients (from birth to 14 years) showed 20~50 percent fewer neuronal densities compared to age-matched controls . The reduction in neuron numbers was also observed in the middle-aged patients . This phenomenon correlates with findings from the fetal brains  and cultured fibroblasts with DS  that showed altered cell proliferation. The arrest of neurogenesis is accompanied with early arrest of brain growth as well as higher frequency of Alzheimer's disease (AD)-like plaque and tangle formation [13, 16, 17]. Also, the brains with DS showed a significant reduction in dendritic spine number in the hippocampus [18, 19]. Alteration in synaptogenesis can be supported by a recent study that the DS model mice show significant changes in spine morphology .
Among a number of DSCR gene products, Dyrk1A is the most attractive protein that shows close association with neuritogenesis. In nerve growth factor-induced PC12 cell neuronal differentiation (a cell line derived from a pheochromocytoma of the rat adrenal medulla), Dyrk1A overexpression prolonged mitogen-activated protein kinase cascade and promoted neurite outgrowth . In contrast, stable overexpression of Dyrk1A in immortalized H19-7 hippocampal neural progenitor cells caused a failure in basic fibroblast growth factor-induced neuronal differentiation . Cortical neurons from Dyrk1A transgenic adult mice also showed a reduction in the length and number of dendrites . Meanwhile, knockdown of Dyrk1A by specific short hairpin RNA in cultured cortical neurons caused a reduction in neurite length and tau-1-positive axons as well as an increase in neurite branching . The compromised neuritogenesis by Dyrk1A knockdown was considered as a consequence of reduced phosphorylation at serine 1392 residue of microtubule-associated protein 1B (MAP1B) and of altered microtubule dynamics . In addition, a potent and specific inhibitor of Dyrk1A, harmine, showed a capacity that can reduce the number of neurites in cultured hippocampal neurons . Although there are many gaps in knowledge due to different experimental systems and approaches, it is obvious that Dyrk1A protein levels may contribute to neurite formation and altered neuritogenesis seen in DS.
Dyrk1A also contributes to regulation of actin dynamics and synaptogenesis. Yeast homologue of Dyrk kinase, Pom1, interacts with Rga4 GTPase-activating protein and regulates Rga4 localization, which is involved in Cdc42 GTPase localization in yeast . RNA interference screen of
One of the major neuropathological features of DS is a sign of early onset of AD-like symptoms, characterized by the formation of amyloid senile plaques (insoluble deposits of β-amyloid) and neurofibrillary tangles (hyperphosphorylated tau aggregates) [16, 17, 30, 31]. Dyrk1A has been intensively investigated in the context of its contribution to hyperphosphorylation of tau that stabilizes microtubules. The phosphorylating capacity of Dyrk1A to threonine 212 residue of tau was first described by
As described above, Dyrk1A is closely associated with regulation of cytoskeletal protein such as tubulin, actin, and microtubule-associated protein tau through phosphorylation of various substrates. A group of substrates that are phosphorylated by Dyrk1A further contributes to regulation of neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation. Although many gaps in knowledge are still remaining, those extensive studies strongly suggest that the approximately 1.5-fold increase of Dyrk1A in the brains with DS may be one of the factors that lead to the neuropathologic features shown in DS patients.
Understanding molecular mechanisms of neuropathological features can offer a rationale for new preventive and therapeutic treatment of DS. One could be that inhibition of Dyrk1A activity from the excessive protein amount in DS may prevent the symptoms or make them less severe. So far, a few potent inhibitors of Dyrk1A have been identified. One of them is epigallocatechin-3-gallate (EGCG), which is the major catechin component of green tea. Treatment of EGCG promoted long-term potentiation of Ts65Dn DS model mice  and rescued the defects of Dyrk1A transgenic mouse brains . Another candidate inhibitor of Dyrk1A is harmine although all Dyrk family proteins can be inhibited by harmine . Treatment of harmine effectively reduced tau phosphorylation in neuroglioma cell line . Although the current version of Dyrk1A inhibitors should be improved to get better specificity and efficacy, understanding molecular links between a strong contributor such as Dyrk1A and neuropathological features of DS and developing potent inhibitors against the identified molecular targets will bring us more closely to new preventive and therapeutic treatment of DS.