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E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice, hence cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
October 15, 2016: Cell Biology International
Ulli Rothweiler, Wenche Stensen, Bjorn-Olav Brandsdal, Johan Isaksson, Frederick Alan Leeson, Richard Alan Engh, John S Svendsen
DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. Based on the observation of selective DYRK1A inhibition by firefly D-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by e...
October 13, 2016: Journal of Medicinal Chemistry
Lyamin Z Bendjeddou, Nadège Loaëc, Benoît Villiers, Eric Prina, Gerald F Späth, Hervé Galons, Laurent Meijer, Nassima Oumata
3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases...
September 22, 2016: European Journal of Medicinal Chemistry
Luis G Rabaneda, Noelia Geribaldi-Doldán, Maribel Murillo-Carretero, Manuel Carrasco, José M Martínez-Salas, Cristina Verástegui, Carmen Castro
Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway...
September 26, 2016: Biochimica et Biophysica Acta
Christophe Labrière, Olivier Lozach, Mélina Blairvacq, Laurent Meijer, Catherine Guillou
Starting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1...
August 31, 2016: European Journal of Medicinal Chemistry
Giada Zurlo, Jianping Guo, Mamoru Takada, Wenyi Wei, Qing Zhang
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer...
September 20, 2016: Biochimica et Biophysica Acta
Kristie I Aamodt, Radhika Aramandla, Judy Brown, Nathalie Fiaschi-Taesch, Peng Wang, Andrew F Stewart, Marcela Brissova, Alvin C Powers
Numerous compounds stimulate rodent β cell proliferation; however, translating these findings to human β cells remains a challenge. To examine human β cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently-labeled β cells with high specificity using both nuclear and cytoplasmic markers...
September 13, 2016: American Journal of Physiology. Endocrinology and Metabolism
J Shirakawa, R N Kulkarni
β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field...
September 2016: Diabetes, Obesity & Metabolism
Liu Yang, Sayantanee Paul, Kenneth G Trieu, Lucas G Dent, Francesca Froldi, Marta Forés, Kaitlyn Webster, Kellee R Siegfried, Shu Kondo, Kieran Harvey, Louise Cheng, Gerardo Jiménez, Stanislav Y Shvartsman, Alexey Veraksa
The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Samantha D McElyea, John M Starbuck, Danika M Tumbleson-Brink, Emily Harrington, Joshua D Blazek, Ahmed Ghoneima, Katherine Kula, Randall J Roper
Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure...
September 5, 2016: Human Molecular Genetics
Jongchan Kim, Ashley N Siverly, Dahu Chen, Min Wang, Yuan Yuan, Yumeng Wang, Hyemin Lee, Jinsong Zhang, William J Muller, Han Liang, Boyi Gan, Xianbin Yang, Yutong Sun, M James You, Li Ma
The invasive and metastatic properties of many human tumors have been associated with upregulation of the microRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here we report the generation of miR-10b-deficient mice in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer...
August 28, 2016: Cancer Research
L J Kay, T K Smulders-Srinivasan, M Soundararajan
The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A...
2016: Advances in Protein Chemistry and Structural Biology
Junhua Geng, Liping Wang, Joo Yeun Lee, Chun-Kan Chen, Karen T Chang
UNLABELLED: The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood...
August 24, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Luan Cen, Yousheng Xiao, Lei Wei, Mingshu Mo, Xiang Chen, Shaomin Li, Xingling Yang, Qinghui Huang, Shaogang Qu, Zhong Pei, Pingyi Xu
α-Synuclein plays important roles in the development of Parkinson's disease (PD) pathologies. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has a wide range of phosphorylation targets including α-synuclein. Posphorylated α-synuclein is more neurotoxic to dopamine (DA) neurons, but little is known about the genetic variation of DYRK1A in patients with PD. The present investigation aimed to explore the possible association of DYRK1A gene with PD in Chinese Han population. A total of 268 PD patients and 268 healthy-matched individuals in Chinese Han population were enrolled...
October 6, 2016: Neuroscience Letters
Mirja N Shaikh, Francisco Gutierrez-Aviño, Jordi Colonques, Julian Ceron, Barbara Hämmerle, Francisco J Tejedor
A key aim of neurodevelopmental research is to understand how precursor cells decide to stop dividing and commence their terminal differentiation at the correct time and place. Here, we show that minibrain (mnb), the Drosophila ortholog of the Down syndrome candidate gene DYRK1A, is transiently expressed in newborn neuronal precursors known as ganglion cells (GCs). Mnb promotes the cell cycle exit of GCs through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27(Kip1) (Cdkn1b)...
September 1, 2016: Development
Jae Bong Lee, Chae Kyoung Yoo, Hee Bok Park, In Cheol Cho, Hyun Tae Lim
The aim of this study was to detect positional candidate genes located within the support interval (SI) regions based on the results of RBC, MCV, and MCH QTL in SSC13, and to verify the correlation between SNPs located in the exonic region of the positional candidate gene and the three genetic traits. The flanking markers of the three QTL SI regions are SW38 and S0215. Within the QTL SI regions, 44 genes were located, and RUNX1, DYRK1A, and KCNJ15 - which are reported to be related to the hematological traits and clinical features of Down syndrome - were selected as positional candidate genes...
August 4, 2016: Asian-Australasian Journal of Animal Sciences
Marie Lawson, Jordi Rodrigo, Blandine Baratte, Thomas Robert, Claire Delehouzé, Olivier Lozach, Sandrine Ruchaud, Stéphane Bach, Jean-Daniel Brion, Mouad Alami, Abdallah Hamze
We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range...
November 10, 2016: European Journal of Medicinal Chemistry
Wael Zeinyeh, Yannick J Esvan, Lionel Nauton, Nadège Loaëc, Laurent Meijer, Vincent Théry, Fabrice Anizon, Francis Giraud, Pascale Moreau
The synthesis of new diversely substituted pyrido[3,4-g]quinazolines is described. The inhibitory potencies of prepared compounds toward a panel of five CMGC protein kinases (CDK5, CLK1, DYRK1A, CK1, GSK3), that are known to play a potential role in Alzheimer's disease, were evaluated. The best overall kinase inhibition profile was found for nitro compound 4 bearing an ethyl group at the 5-position.
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
Fiorenza Stagni, Andrea Giacomini, Marco Emili, Stefania Trazzi, Sandra Guidi, Martina Sassi, Elisabetta Ciani, Roberto Rimondini, Renata Bartesaghi
Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype...
October 1, 2016: Neuroscience
Arnaud Duchon, Yann Herault
Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer's disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits...
2016: Frontiers in Behavioral Neuroscience
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