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https://www.readbyqxmd.com/read/28775333/dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-gene-transcription-is-regulated-by-myocyte-enhancer-factor-2d
#1
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
#2
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...
August 2, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28756311/neurogenesis-impairment-an-early-developmental-defect-in-down-syndrome
#3
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
#4
Tandekile Lubelwana Hafver, Pimthanya Wanichawan, Ornella Manfra, Gustavo Antonio de Souza, Marianne Lunde, Marita Martinsen, William Edward Louch, Ole Mathias Sejersted, Cathrine Rein Carlson
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 mass spectrometry 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 with His-TF-NCX1cyt recombinant protein as bait...
July 28, 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
#5
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 of GLI1 suggesting a possible mechanistic role in modulating its translocation...
July 20, 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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28562327/the-protein-kinase-mbk-1-contributes-to-lifespan-extension-in-daf-2-mutant-and-germline-deficient-caenorhabditis-elegans
#13
Hildegard I D Mack, Peichuan Zhang, Bryan R Fonslow, John R Yates
In Caenorhabditis elegans, reduction of insulin/IGF-1 like signaling and loss of germline stem cells both increase lifespan by activating the conserved transcription factor DAF-16 (FOXO). While the mechanisms that regulate DAF-16 nuclear localization in response to insulin/IGF-1 like signaling are well characterized, the molecular pathways that act in parallel to regulate DAF-16 transcriptional activity, and the pathways that couple DAF-16 activity to germline status, are not fully understood at present. Here, we report that inactivation of MBK-1, the C...
May 25, 2017: Aging
https://www.readbyqxmd.com/read/28561591/development-of-selective-clk1-and-4-inhibitors-for-cellular-depletion-of-cancer-relevant-proteins
#14
Ahmed K ElHady, Mohammad Abdel-Halim, Ashraf H Abadi, Matthias Engel
In cancer cells, kinases of the Clk family control the supply of full-length, functional mRNAs coding for a variety of proteins essential to cell growth and survival. Thus, inhibition of Clks might become a novel anticancer strategy, leading to a selective depletion of cancer-relevant proteins after turnover. On the basis of a Weinreb amide hit compound, we designed and synthesized a diverse set of methoxybenzothiophene-2-carboxamides, of which the N-benzylated derivative showed enhanced Clk1 inhibitory activity...
May 31, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28540658/overexpression-of-the-dyrk1a-gene-dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-induces-alterations-of-the-serotoninergic-and-dopaminergic-processing-in-murine-brain-tissues
#15
Jacqueline London, Claude Rouch, Linh Chi Bui, Elodie Assayag, Benoit Souchet, Fabrice Daubigney, Hind Medjaoui, Serge Luquet, Christophe Magnan, Jean Maurice Delabar, Julien Dairou, Nathalie Janel
Trisomy 21 (T21) or Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and affects around 5 million persons worldwide. Neuroanatomical phenotypes associated with T21 include slight reduction of brain size and weight, abnormalities in several brain areas including spines dysgenesis, dendritic morphogenesis, and early neuroanatomical characteristics of Alzheimer's disease. Monoamine neurotransmitters are involved in dendrites development, functioning of synapses, memory consolidation, and their levels measured in the cerebrospinal fluid, blood, or brain areas that are modified in individuals with T21...
May 25, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28496994/novel-causative-variants-in-dyrk1a-kars-and-kat6a-associated-with-intellectual-disability-and-additional-phenotypic-features
#16
Clark R Murray, Samantha N Abel, Matthew B McClure, Joseph Foster, Maria I Walke, Parul Jayakar, Guney Bademci, Mustafa Tekin
Patients with unclear patterns of developmental and cognitive delay may go years without a definitive diagnosis despite extensive testing due to overlapping phenotypes of many genetic disorders. In this study, we identified causative variants in DYRK1A, KARS, or KAT6A in four individuals with global developmental delay and various findings including microcephaly and sensorineural hearing loss using whole exome sequencing. We present the cognitive, neurologic, and physical findings of four individuals to expand the clinical knowledge of possible features of the phenotypes of three rare genetic disorders...
June 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28487075/n-1h-pyrazol-3-yl-quinazolin-4-amines-as-a-novel-class-of-casein-kinase-1%C3%AE-%C3%AE%C2%B5-inhibitors-synthesis-biological-evaluation-and-molecular-modeling-studies
#17
Chandrabose Karthikeyan, Pramod Jharia, Digambar Kumar Waiker, Amy Catherine Nusbaum, Haneen Amawi, Erin Marie Kirwen, Ryann Christman, Sri Krishna Chaitanya Arudra, Laurent Meijer, Amit K Tiwari, Piyush Trivedi
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28425089/high-diagnostic-yield-of-clinically-unidentifiable-syndromic-growth-disorders-by-targeted-exome-sequencing
#18
Yoo-Mi Kim, Yun-Jin Lee, Jae Hong Park, Hyoung-Doo Lee, Chong Kun Cheon, Su-Young Kim, Jae-Yeon Hwang, Ja-Hyun Jang, Han-Wook Yoo
As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea...
April 20, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28408219/developing-dyrk-inhibitors-derived-from-the-meridianins-as-a-means-of-increasing-levels-of-nfat-in-the-nucleus
#19
Simon J Shaw, Dane A Goff, Nan Lin, Rajinder Singh, Wei Li, John McLaughlin, Kristen A Baltgalvis, Donald G Payan, Todd M Kinsella
A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a inhibitors...
March 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28377597/dyrk1a-overexpression-leads-to-increase-of-3r-tau-expression-and-cognitive-deficits-in-ts65dn-down-syndrome-mice
#20
Xiaomin Yin, Nana Jin, Jianhua Shi, Yanchong Zhang, Yue Wu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10...
April 4, 2017: Scientific Reports
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