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https://www.readbyqxmd.com/read/29127398/overexpression-of-dyrk1a-a-down-syndrome-candidate-gene-impairs-primordial-germ-cells-maintenance-and-migration-in-zebrafish
#1
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
https://www.readbyqxmd.com/read/29071296/data-on-peptides-identified-by-mass-spectrometry-analysis-of-in-vitro-dyrk1a-mediated-phosphorylation-sites-on-gli1
#2
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
https://www.readbyqxmd.com/read/29039762/marine-derived-2-aminoimidazolone-alkaloids-leucettamine-b-related-polyandrocarpamines-inhibit-mammalian-and-protozoan-dyrk-clk-kinases
#3
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
https://www.readbyqxmd.com/read/29034068/clinical-phenotype-of-asd-associated-dyrk1a-haploinsufficiency
#4
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
https://www.readbyqxmd.com/read/29021890/zebrafish-knockout-of-down-syndrome-gene-dyrk1a-shows-social-impairments-relevant-to-autism
#5
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
https://www.readbyqxmd.com/read/28944229/targeting-trisomic-treatments-optimizing-dyrk1a-inhibition-to-improve-down-syndrome-deficits
#6
REVIEW
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
https://www.readbyqxmd.com/read/28884684/inhibition-of-dyrk1a-disrupts-neural-lineage-specificationin-human-pluripotent-stem-cells
#7
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
https://www.readbyqxmd.com/read/28874550/prenatal-neurogenesis-induction-therapy-normalizes-brain-structure-and-function-in-down-syndrome-mice
#8
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
https://www.readbyqxmd.com/read/28775333/dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-gene-transcription-is-regulated-by-myocyte-enhancer-factor-2d
#9
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
https://www.readbyqxmd.com/read/28766366/dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-dyrk1a-inhibitors-a-survey-of-recent-patent-literature
#10
REVIEW
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
https://www.readbyqxmd.com/read/28756311/neurogenesis-impairment-an-early-developmental-defect-in-down-syndrome
#11
REVIEW
Fiorenza Stagni, Andrea Giacomini, Marco Emili, Sandra Guidi, Renata Bartesaghi
Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype...
July 26, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28755400/mapping-the-in-vitro-interactome-of-cardiac-sodium-na-calcium-ca-2-exchanger-1-ncx1
#12
Tandekile Lubelwana Hafver, Pimthanya Wanichawan, Ornella Manfra, Gustavo Antonio de Souza, Marianne Lunde, Marita Martinsen, William Edward Louch, Ole Mathias Sejersted, Cathrine Rein Carlson
The sodium (Na(+) )-calcium (Ca(2+) ) exchanger 1 (NCX1) is an antiporter membrane protein encoded by the SLC8A1 gene. In the heart, it maintains cytosolic Ca(2+) homeostasis, serving as the primary mechanism for Ca(2+) extrusion during relaxation. Dysregulation of NCX1 is observed in end-stage human heart failure. In this study, we used affinity purification coupled with MS in rat left ventricle lysates to identify novel NCX1 interacting proteins in the heart. Two screens were conducted using: (1) anti-NCX1 against endogenous NCX1 and (2) anti-His (where His is histidine) with His-trigger factor-NCX1cyt recombinant protein as bait...
September 2017: Proteomics
https://www.readbyqxmd.com/read/28735864/identification-of-a-dyrk1a-mediated-phosphorylation-site-within-the-nuclear-localization-sequence-of-the-hedgehog-transcription-factor-gli1
#13
Ben K Ehe, David R Lamson, Michael Tarpley, Rob U Onyenwoke, Lee M Graves, Kevin P Williams
GLI1 is a key downstream transcription effector of the Hedgehog (Hh) signaling pathway that is involved in promoting cell growth, differentiation and tissue patterning in embryonic development. GLI1 over-activation and its nuclear localization has also been linked to the increased aggressiveness of a number of cancers. It has previously been demonstrated that DYRK1A (dual-specificity tyrosine-regulated kinase 1A) can phosphorylate GLI1 and promote GLI1 nuclear localization and its transcriptional activity. Utilizing recombinant human GLI1 and DYRK1A proteins and phospho-peptide mass spectrometry, we demonstrated that GLI1 is phosphorylated by DYRK1A at Ser408, a phospho-site that falls within the putative nuclear localization sequence (NLS) of GLI1, suggesting a possible mechanistic role in modulating its translocation...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28735747/a-requirement-for-mena-an-actin-regulator-in-local-mrna-translation-in-developing-neurons
#14
Marina Vidaki, Frauke Drees, Tanvi Saxena, Erwin Lanslots, Matthew J Taliaferro, Antonios Tatarakis, Christopher B Burge, Eric T Wang, Frank B Gertler
During neuronal development, local mRNA translation is required for axon guidance and synaptogenesis, and dysregulation of this process contributes to multiple neurodevelopmental and cognitive disorders. However, regulation of local protein synthesis in developing axons remains poorly understood. Here, we uncover a novel role for the actin-regulatory protein Mena in the formation of a ribonucleoprotein complex that involves the RNA-binding proteins HnrnpK and PCBP1 and regulates local translation of specific mRNAs in developing axons...
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28733602/distinct-selective-forces-and-neanderthal-introgression-shaped-genetic-diversity-at-genes-involved-in-neurodevelopmental-disorders
#15
Alessandra Mozzi, Diego Forni, Rachele Cagliani, Uberto Pozzoli, Mario Clerici, Manuela Sironi
In addition to high intelligence, humans evolved specialized social-cognitive skills, which are specifically affected in children with autism spectrum disorder (ASD). Genes affected in ASD represent suitable candidates to study the evolution of human social cognition. We performed an evolutionary analysis on 68 genes associated to neurodevelopmental disorders; our data indicate that genetic diversity was shaped by distinct selective forces, including natural selection and introgression from archaic hominins...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28674290/elucidating-pathogenic-mechanisms-of-early-onset-alzheimer-s-disease-in-down-syndrome-patients
#16
REVIEW
Masashi Asai, Takashi Kawakubo, Ryotaro Mori, Nobuhisa Iwata
 Down syndrome (DS) patients demonstrate the neuropathology of Alzheimer's disease (AD) characterized by the formation of senile plaques and neurofibrillary tangles by age 40-50 years. It has been considered for a number of years that 1.5-fold expression of the gene for the amyloid precursor protein (APP) located on chromosome 21 leading to overproduction of amyloid-β peptide (Aβ) results in the early onset of AD in adults with DS. However, the mean age of onset of familial AD with the Swedish mutation on APP which has high affinity for β-secretase associated with a dramatic increase in Aβ production is about 55 years...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28674289/molecular-mechanism-underlying-abnormal-differentiation-of-neural-progenitor-cells-in-the-developing-down-syndrome-brain
#17
REVIEW
Nobuhiro Kurabayashi, Kamon Sanada
 Down syndrome (DS) is caused by trisomy for human chromosome 21. Individuals with DS commonly exhibit mental retardation, which is associated with abnormal brain development. In the neocortex of the DS brain, the density of neurons is markedly reduced, whereas that of astrocytes is increased. Similar to abnormalities seen in DS brains, mouse models of DS show deficits in brain development, and neural progenitor cells that give rise to neurons and glia show dysregulation in their differentiation. These suggest that the dysregulation of progenitor fate choices contributes to alterations in the numbers of neurons and astrocytes in the DS brain...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28650432/corrigendum-a-dual-specificity-kinase-dyrk1a-as-a-potential-therapeutic-target-for-head-and-neck-squamous-cell-carcinoma
#18
Aneesha Radhakrishnan, Vishalakshi Nanjappa, Remya Raja, Gajanan Sathe, Vinuth N Puttamallesh, Ankit P Jain, Sneha M Pinto, Sai A Balaji, Sandip Chavan, Nandini A Sahasrabuddhe, Premendu P Mathur, Mahesh M Kumar, T S Keshava Prasad, Vani Santosh, Geethanjali Sukumar, Joseph A Califano, Annapoorni Rangarajan, David Sidransky, Akhilesh Pandey, Harsha Gowda, Aditi Chatterjee
This corrects the article DOI: 10.1038/srep36132.
June 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28647555/normalizing-the-gene-dosage-of-dyrk1a-in-a-mouse-model-of-down-syndrome-rescues-several-alzheimer-s-disease-phenotypes
#19
Susana García-Cerro, Noemí Rueda, Verónica Vidal, Sara Lantigua, Carmen Martínez-Cué
The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology...
June 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28632203/combined-assessment-of-dyrk1a-bdnf-and-homocysteine-levels-as-diagnostic-marker-for-alzheimer-s-disease
#20
N Janel, P Alexopoulos, A Badel, F Lamari, A C Camproux, J Lagarde, S Simon, C Feraudet-Tarisse, P Lamourette, M Arbones, J L Paul, B Dubois, M C Potier, M Sarazin, J M Delabar
Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls...
June 20, 2017: Translational Psychiatry
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