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Yassan Abdolazimi, Sooyeon Lee, Haixia Xu, Paul Allegretti, Timothy M Horton, Benjamin Yeh, Hannah P Moeller, Robert J Nichols, David McCutcheon, Aryaman Shalizi, Mark Smith, Neali A Armstrong, Justin P Annes
Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition...
March 5, 2018: Endocrinology
Mirja N Shaikh, Francisco J Tejedor
The Down syndrome and microcephaly related gene Mnb/Dyrk1A encodes an evolutionary conserved protein kinase subfamily that plays important roles in neurodevelopment. minibrain (mnb) mutants of Drosophila melanogaster (Dm) exhibit reduced adult brains due to neuronal deficits generated during larval development. These deficits are the consequence of the apoptotic cell death of numerous neuronal precursors that fail to properly exit the cell cycle and differentiate. We have recently found that in both the Dm larval brain and the embryonic vertebrate central nervous system (CNS), a transient expression of Mnb/Dyrk1A promotes the cell cycle exit of newborn neuronal precursors by upregulating the expression of the cyclin-dependent kinase inhibitor p27kip1 (called Dacapo in Dm)...
March 2018: Journal of Neurogenetics
Fernanda Neumann, Stéphanie Gourdain, Christelle Albac, Alain D Dekker, Linh Chi Bui, Julien Dairou, Isabelle Schmitz-Afonso, Nathalie Hue, Fernando Rodrigues-Lima, Jean M Delabar, Marie-Claude Potier, Jean-Pierre Le Caër, David Touboul, Benoît Delatour, Kevin Cariou, Robert H Dodd
Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line)...
February 12, 2018: Scientific Reports
Wei Zhang, Li Qian, Maya Deyssenroth, Luca Lambertini, Jackie Finik, Jacob Ham, Yongling Huang, Kenji J Tsuchiya, Patricia Pehme, Jessica Buthmann, Sachiko Yoshida, Jia Chen, Yoko Nomura
Prenatal maternal stress increases the risk for negative developmental outcomes in offspring, however the underlying biological mechanisms remain largely unexplored. In this study, alterations in placental gene expression associated with maternal stress were examined to elucidate potential underlying epi/genetic mechanisms. Expression levels of 40 selected genes involved in regulating fetal HPA-axis and neurodevelopment were profiled in placental tissues collected from a birth cohort established around the time of Superstorm Sandy...
February 9, 2018: Journal of Neuroendocrinology
Melissa J Alldred, Helen M Chao, Sang Han Lee, Judah Beilin, Brian E Powers, Eva Petkova, Barbara J Strupp, Stephen D Ginsberg
Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS...
February 2, 2018: Hippocampus
Rosanna Meine, Walter Becker, Hannes Falke, Lutz Preu, Nadège Loaëc, Laurent Meijer, Conrad Kunick
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer's disease. The selective DYRK1A inhibitor 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1H-indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors...
January 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Hiroyuki Miyamoto, Kazuhiro Yamakawa
Mutations and copy number variants affecting DYRK1A gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1A are among the most frequent genetic causes of neurodevelopmental disorders including autism spectrum disorder (ASD) associated with microcephaly, febrile seizures and severe speech acquisition delay. Here we developed a mouse model harboring a frame-shift mutation in Dyrk1a resulting in a protein truncation and elimination of its kinase activity site. Dyrk1a+/- mice showed significant impairments in cognition and cognitive flexibility, communicative ultrasonic vocalizations, and social contacts...
February 2018: Neurobiology of Disease
Susana García-Cerro, Verónica Vidal, Sara Lantigua, Maria Teresa Berciano, Miguel Lafarga, Pedro Ramos-Cabrer, Daniel Padro, Noemí Rueda, Carmen Martínez-Cué
Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations...
February 2018: Neurobiology of Disease
Laura Llorach-Pares, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Conxita Avila
Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT)...
November 27, 2017: Marine Drugs
Hedwig S Kruitwagen, Bart Westendorp, Cornelia S Viebahn, Krista Post, Monique E van Wolferen, Loes A Oosterhoff, David A Egan, Jean-Maurice Delabar, Mathilda J Toussaint, Baukje A Schotanus, Alain de Bruin, Jan Rothuizen, Louis C Penning, Bart Spee
Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay...
January 15, 2018: Stem Cells and Development
Yanyan Liu, Ziyuan Lin, Mingfeng Liu, He Wang, Huaqin Sun
DYRK1A, located on chromosome 21, is a major candidate gene of Down syndrome (DS, trisomy21), and its overexpression is associated with abnormal phenotype of Down syndrome patients. The defects of gonads and germ cells in Down Syndrome suggest that overexpression of DYRK1A has potential effect on primordial germ cells (PGCs) development. Human and zebrafish DYRK1A protein sequence possess 75.6% similarity and same function domains, suggesting the evolutional conservation. Here, we used zebrafish model to detect the definite role of excessive expression of DYRK1A in PGCs development during embryogenesis...
November 10, 2017: Scientific Reports
Ben K Ehe, David R Lamson, Michael Tarpley, Rob U Onyenwoke, Lee M Graves, Kevin P Williams
The data presented in this article support the accompanying research article "Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1" (Ehe et al., 2017) [1]. Although it has been demonstrated that DYRK1A (dual-specificity tyrosine-regulated kinase 1A) can phosphorylate the hedgehog pathway transcription factor GLI1 (GLIoma-associated oncogene homolog 1) and promote its nuclear localization, the DYRK1A-mediated sites of phosphorylation on GLI1 involved were not fully known...
December 2017: Data in Brief
Nadège Loaëc, Eletta Attanasio, Benoît Villiers, Emilie Durieu, Tania Tahtouh, Morgane Cam, Rohan A Davis, Aline Alencar, Mélanie Roué, Marie-Lise Bourguet-Kondracki, Peter Proksch, Emmanuelle Limanton, Solène Guiheneuf, François Carreaux, Jean-Pierre Bazureau, Michelle Klautau, Laurent Meijer
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome...
October 17, 2017: Marine Drugs
Rachel K Earl, Tychele N Turner, Heather C Mefford, Caitlin M Hudac, Jennifer Gerdts, Evan E Eichler, Raphael A Bernier
BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981)...
2017: Molecular Autism
Oc-Hee Kim, Hyun-Ju Cho, Enna Han, Ted Inpyo Hong, Krishan Ariyasiri, Jung-Hwa Choi, Kyu-Seok Hwang, Yun-Mi Jeong, Se-Yeol Yang, Kweon Yu, Doo-Sang Park, Hyun-Woo Oh, Erica E Davis, Charles E Schwartz, Jeong-Soo Lee, Hyung-Goo Kim, Cheol-Hee Kim
BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism...
2017: Molecular Autism
Megan Stringer, Charles R Goodlett, Randall J Roper
Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials...
September 2017: Molecular Genetics & Genomic Medicine
Stephanie F Bellmaine, Dmitry A Ovchinnikov, David T Manallack, Claire E Cuddy, Andrew G Elefanty, Edouard G Stanley, Ernst J Wolvetang, Spencer J Williams, Martin Pera
Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, is known to affect neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show here that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development...
September 8, 2017: ELife
Akiko Nakano-Kobayashi, Tomonari Awaya, Isao Kii, Yuto Sumida, Yukiko Okuno, Suguru Yoshida, Tomoe Sumida, Haruhisa Inoue, Takamitsu Hosoya, Masatoshi Hagiwara
Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
Pin Wang, Luanluan Wang, Long Chen, Xiulian Sun
Dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A) is localized in the Down syndrome critical region of chromosome 21. As a candidate gene responsible for learning defects associated with Down syndrome and Alzheimer's disease (AD), DYRK1A has been implied to play pivotal roles in cell proliferation and brain development. MEF2D, a member of the myocyte-specific enhancer factor 2 (MEF2) family of transcription factors, was proved to be in control of neuronal cell differentiation and development...
August 3, 2017: Scientific Reports
Thu Lan Nguyen, Corinne Fruit, Yann Hérault, Laurent Meijer, Thierry Besson
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a eukaryotic serine-threonine protein kinase belonging to the CMGC group. DYRK1A hyperactivity appears to contribute to the development of a number of human malignancies and to cognitive deficits observed in Down syndrome and Alzheimer's disease. As a result, the DYRK1A kinase represents an attractive target for the synthesis and optimization of pharmacological inhibitors of potential therapeutic interest. Like most tyrosine kinase inhibitors developed up to the market, DYRK1A inhibitors are essentially acting by competing with ATP for binding at the catalytic site of the kinase...
November 2017: Expert Opinion on Therapeutic Patents
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