Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain (mnb) and the mammalian ortholog Dyrk1a target genes of sNPF and NPY signaling and regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, as well as increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals.

The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the c-secretase complex in the generation of b-amyloid (Ab), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Ab production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Ab is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr 354 and that this phosphorylation increases c-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Ab pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.

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Background:The regulatory mechanism of GSK3␤ activity is not yet fully understood. Results: Dyrk1A inactivates GSK3␤ by phosphorylation at Thr 356 , which may contribute to an obesity-resistant phenotype. Conclusion: Dyrk1A-mediated phosphorylation is an alternative pathway for GSK3␤ inactivation. Significance: Understanding the mechanism regulating GSK3␤ activity is crucial for developing new therapies against GSK3␤-associated diseases, including obesity.

J. Neurochem. (2012) 122, 1081–1091. Abstract Dual‐specificity tyrosine(Y)‐phosphorylation‐regulated kinase 1A (Dyrk1A) is a protein kinase that might be responsible for mental retardation and early onset of Alzheimer’s disease in Down’s syndrome patients. Dyrk1A plays a role in many cellular pathways through phosphorylation of diverse substrate proteins; however, its role in synaptic vesicle exocytosis is poorly understood. Munc18‐1, a central regulator of neurotransmitter release, interacts with Syntaxin 1 and X11α. Syntaxin 1 is a key soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor protein involved in synaptic vesicle docking/fusion events, and X11α modulates amyloid precursor protein processing and β amyloid generation. In this study, we demonstrate that Dyrk1A interacts with and phosphorylates Munc18‐1 at the Thr479 residue. The phosphorylation of Munc18‐1 at Thr479 by Dyrk1A stimulated binding of Munc18‐1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho‐Thr479‐Munc18‐1 were enhanced in the brains of transgenic mice over‐expressing Dyrk1A protein, providing in vivo evidence of Munc18‐1 phosphorylation by Dyrk1A. These results reveal a link between Munc18‐1 and Dyrk1A in synaptic vesicle trafficking and amyloid precursor protein processing, suggesting that up‐regulated Dyrk1A in Down’s syndrome and Alzheimer’s disease brains may contribute to some pathological features, including synaptic dysfunction and cognitive defect through abnormal phosphorylation of Munc18‐1.

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Mucin hypersecretion and overproduction are frequent manifestations of respiratory disease. Determining the physiological function of airway mucin is presently considered more important than identifying the relevant signaling pathways. The lack of a full-length human mucin 8 (MUC8) cDNA sequence has hindered the generation of a Muc8 knockout mouse line. Thus, the precise physiological functions of MUC8 are unclear. Herein, we investigated the function of MUC8 using a small-interfering RNA (siRNA)-mediated genetic silencing approach in human airway epithelial cells. Herein, intracellular IL-1␣ production was stimulated by an ATP/P2Y2 complex. While ATP/P2Y2 increased IL-1␣ secretion in a time-dependent manner, treatment with P2Y2-specific siRNA significantly decreased IL-1␣ secretion. Moreover, ATP increased P2Y2-mediated upregulation of MUC8 expression; however, IL-1␣ significantly decreased the extent to which ATP/P2Y2 upregulated MUC8 expression. Interestingly, treatment with MUC8-specific siRNA decreased the production of anti-inflammatory cytokines (TGF-␤ and IL-1 receptor antagonist) and increased the production of inflammatory cytokines (IL-1␣ and IL-6) in our system. In addition, siRNA-mediated knockdown of MUC8 expression dramatically increased the secretion of inflammatory chemokines and resulted in an approximately threefold decrease in cell chemotaxis. We propose that MUC8 may function as an anti-inflammatory mucin that participates in inflammatory response by attracting immune cells/ cytokines to the site of inflammation. Our results provide new insight into the physiological function of MUC8 and enhance our understanding of mucin overproduction during airway inflammation. adenosine 5=-triphosphate; mucin 8; inflammatory cytokines; smallinterfering ribonucleic acid

Down syndrome (DS) results from overexpressed genes on an extra copy of human chromosome 21. Among various phenotypes seen in DS patients, mental retardation, such as learning and memory deficits, is a major factor that prevents DS individuals from leading fully independent lives. The Dyrk1A gene that plays a critical role in neurodevelopment has been isolated from chromosome 21, and transgenic mice with over-expression of Dyrk1A show severe hippocampal dependent learning and memory defects. In the present study, as an initial step to test the treatment of Dyrk1A dependent mental retardation phenotypes in model animals, we isolated human Dyrk1A specific lentiviral short hairpin RNA (shRNA) that inhibits the exogenous human Dyrk1A expression, but not the endogenous mouse expression in transgenic mice with human Dyrk1A overexpression. This limited and specific repression of exogenous human Dyrk1A will prove to be valuable information, if Dyrk1A dependent learning and memory defects in DS patients could be treated or at least ameliorated in vivo.