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https://www.readbyqxmd.com/read/28641077/inhibition-of-early-growth-response-1-in-the-hippocampus-alleviates-neuropathology-and-improves-cognition-in-an-alzheimer-model-with-plaques-and-tangles
#1
Xike Qin, Yunling Wang, Hemant K Paudel
A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28638064/quantitative-phosphoproteomics-reveals-a-role-for-collapsin-response-mediator-protein-2-in-pdgf-induced-cell-migration
#2
Adil R Sarhan, Justyna Szyroka, Shabana Begum, Michael G Tomlinson, Neil A Hotchin, John K Heath, Debbie L Cunningham
The Platelet Derived Growth Factor (PDGF) family of ligands have well established functions in the induction of cell proliferation and migration during development, tissue homeostasis and interactions between tumours and stroma. However, the mechanisms by which these actions are executed are incompletely understood. Here we report a differential phosphoproteomics study, using a SILAC approach, of PDGF-stimulated mouse embryonic fibroblasts (MEFs). 116 phospho-sites were identified as up-regulated and 45 down-regulated in response to PDGF stimulation...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634551/mechanisms-and-consequences-of-dopamine-depletion-induced-attenuation-of-the-spinophilin-neurofilament-medium-interaction
#3
Andrew C Hiday, Michael C Edler, Asma B Salek, Cameron W Morris, Morrent Thang, Tyler J Rentz, Kristie L Rose, Lisa M Jones, Anthony J Baucum
Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28611552/a-novel-mutation-in-pitx2-in-a-patient-with-axenfeld-rieger-syndrome
#4
Susan J Hassed, Shibo Li, Weihong Xu, Ashley C Taylor
Axenfeld-Rieger syndrome is a rare autosomal dominant condition. Anomalies include anterior segment dysgenesis of the eye, dental anomalies, maxillary hypoplasia, periumbilical anomalies, and congenital heart defects. We report a patient with Peters anomaly, dysmorphic features, congenital heart defect, umbilical hernia, short stature, and developmental delay. Diagnostic sequencing of 23 genes known to be causally related to the condition was performed on the patient, parents, and maternal grandparents. A variant of uncertain significance in PITX2 was identified...
March 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/28597249/differential-regulation-of-protein-phosphatase-1-pp1-isoforms-in-human-heart-failure-and-atrial-fibrillation
#5
Stefanie Meyer-Roxlau, Simon Lämmle, Annett Opitz, Stephan Künzel, Julius P Joos, Stefan Neef, Karolina Sekeres, Samuel Sossalla, Friedrich Schöndube, Konstantin Alexiou, Lars S Maier, Dobromir Dobrev, Kaomei Guan, Silvio Weber, Ali El-Armouche
Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1α, β, and γ in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of β-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression...
July 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28579948/modulation-of-low-voltage-activated-inward-current-permeable-to-sodium-and-calcium-by-darpp-32-drives-spontaneous-firing-of-insect-octopaminergic-neurosecretory-cells
#6
Bruno Lapied, Antoine Defaix, Maria Stankiewicz, Eléonore Moreau, Valérie Raymond
Identification of the different intracellular pathways that control phosphorylation/dephosphorylation process of ionic channels represents an exciting alternative approach for studying the ionic mechanisms underlying neuronal pacemaker activity. In the central nervous system of the cockroach Periplaneta americana, octopaminergic neurons, called dorsal unpaired median (DUM; DUM neurons), generate spontaneous repetitive action potentials. Short-term cultured adult DUM neurons isolated from the terminal abdominal ganglion (TAG) of the nerve cord were used to study the regulation of a tetrodotoxin-sensitive low-voltage-activated (LVA) channel permeable to sodium and calcium (Na/Ca), under whole cell voltage- and current-clamp conditions...
2017: Frontiers in Systems Neuroscience
https://www.readbyqxmd.com/read/28576472/redirecting-sr-protein-nuclear-trafficking-through-an-allosteric-platform
#7
Brandon E Aubol, Kendra L Hailey, Laurent Fattet, Patricia A Jennings, Joseph A Adams
Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism...
May 31, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28528309/maintenance-of-claudin-3-expression-and-the-barrier-functions-of-intercellular-junctions-in-parotid-acinar-cells-via-the-inhibition-of-src-signaling
#8
Megumi Yokoyama, Takanori Narita, Hajime Sakurai, Osamu Katsumata-Kato, Hiroshi Sugiya, Junko Fujita-Yoshigaki
OBJECTIVES: Salivary acinar and duct cells show different expression patterns of claudins, which may reflect their different functions. To study the role of claudins in saliva secretion, we examined alterations in the expression patterns of cell adhesion molecules in parotid glands of γ-irradiated rats and analyzed the influence of those changes on intercellular barrier function using primary cultures of parotid acinar cells. DESIGN: Rats were γ-irradiated with doses of 5, 15 or 20Gy, and expression levels of cell adhesion molecules were examined by immunoblotting analysis...
May 15, 2017: Archives of Oral Biology
https://www.readbyqxmd.com/read/28526544/interleukin-18-gene-deletion-protects-against-sepsis-induced-cardiac-dysfunction-by-inhibiting-pp2a-activity
#9
Yoshitaka Okuhara, Shunichi Yokoe, Toshihiro Iwasaku, Akiyo Eguchi, Koichi Nishimura, Wen Li, Makiko Oboshi, Yoshiro Naito, Toshiaki Mano, Michio Asahi, Haruki Okamura, Tohru Masuyama, Shinichi Hirotani
BACKGROUND: Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. METHODS AND RESULTS: Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS...
May 4, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28522851/mouse-rif1-is-a-regulatory-subunit-of-protein-phosphatase-1-pp1
#10
Rasa Sukackaite, Daniela Cornacchia, Malene Ringkjøbing Jensen, Philippe J Mas, Martin Blackledge, Elin Enervald, Guangyou Duan, Tania Auchynnikava, Maja Köhn, Darren J Hart, Sara B C Buonomo
Rif1 is a conserved protein that plays essential roles in orchestrating DNA replication timing, controlling nuclear architecture, telomere length and DNA repair. However, the relationship between these different roles, as well as the molecular basis of Rif1 function is still unclear. The association of Rif1 with insoluble nuclear lamina has thus far hampered exhaustive characterization of the associated protein complexes. We devised a protocol that overcomes this problem, and were thus able to discover a number of novel Rif1 interactors, involved in chromatin metabolism and phosphorylation...
May 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28506997/the-phosphatase-pgam5-antagonizes-wnt-%C3%AE-catenin-signaling-in-embryonic-anterior-posterior-axis-patterning
#11
Verena Rauschenberger, Dominic B Bernkopf, Sabrina Krenn, Kowcee Jalal, Jens Heller, Jürgen Behrens, Marc Gentzel, Alexandra Schambony
The scaffold protein Dishevelled is a central intracellular component of Wnt signaling pathways. Various kinases have been described that regulate and modulate Wnt signaling through phosphorylation of Dishevelled. However, besides general protein phosphatases 1 and 2 (PP1 and PP2), no specific protein phosphatases have been identified. Here, we report on the identification and functional characterization of the protein phosphatase Pgam5 in vitro and in vivo in Xenopus Pgam5 is a novel antagonist of Wnt/β-Catenin signaling in human cells and Xenopus embryogenesis...
June 15, 2017: Development
https://www.readbyqxmd.com/read/28497199/arachidonic-acid-induces-are-nrf2-dependent-heme-oxygenase-1-transcription-in-rat-brain-astrocytes
#12
Chih-Chung Lin, Chien-Chung Yang, Yu-Wen Chen, Li-Der Hsiao, Chuen-Mao Yang
Arachidonic acid (AA) is a major product of phospholipid hydrolysis catalyzed by phospholipase A2 during neurodegenerative diseases. AA exerts as a second messenger to regulate various signaling components which may be involved in different pathophysiological processes. Astrocytes are the main types of CNS resident cells which maintain and support the physiological function of brain. AA has been shown to induce ROS generation through activation of NADPH oxidases (Noxs) which may play a key role in the expression of heme oxygenase-1 (HO-1)...
May 11, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28492545/chronically-stressed-or-stress-preconditioned-neurons-fail-to-maintain-stress-granule-assembly
#13
Tatyana A Shelkovnikova, Pasquale Dimasi, Michail S Kukharsky, Haiyan An, Annamaria Quintiero, Claire Schirmer, Luc Buée, Marie-Christine Galas, Vladimir L Buchman
Dysregulation of stress granules (SGs) and their resident proteins contributes to pathogenesis of a number of (neuro)degenerative diseases. Phosphorylation of eIF2α is an event integrating different types of cellular stress and it is required for SG assembly. Phosphorylated eIF2α (p-eIF2α) is upregulated in the nervous system in some neurodegenerative conditions. We found that increasing p-eIF2α level by proteasomal inhibition in cultured cells, including mouse and human neurons, before a SG-inducing stress ('stress preconditioning'), limits their ability to maintain SG assembly...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28486561/myosin-phosphatase-and-rhoa-activated-kinase-modulate-neurotransmitter-release-by-regulating-snap-25-of-snare-complex
#14
Dániel Horváth, István Tamás, Adrienn Sipos, Zsuzsanna Darula, Bálint Bécsi, Dénes Nagy, Judit Iván, Ferenc Erdődi, Beáta Lontay
Reversible phosphorylation of neuronal proteins plays an important role in the regulation of neurotransmitter release. Myosin phosphatase holoenzyme (MP) consists of a protein phosphatase-1 (PP1) catalytic subunit (PP1c) and a regulatory subunit, termed myosin phosphatase targeting subunit (MYPT1). The primary function of MP is to regulate the phosphorylation level of contractile proteins; however, recent studies have shown that MP is localized to neurons, and is also involved in the mediation of neuronal processes...
2017: PloS One
https://www.readbyqxmd.com/read/28479321/ska3-phosphorylated-by-cdk1-binds-ndc80-and-recruits-ska-to-kinetochores-to-promote-mitotic-progression
#15
Qian Zhang, Sushama Sivakumar, Yujue Chen, Haishan Gao, Lu Yang, Zhu Yuan, Hongtao Yu, Hong Liu
The spindle and kinetochore-associated (Ska) protein complex is required for accurate chromosome segregation during mitosis [1-6] and consists of two copies each of Ska1, Ska2, and Ska3 proteins [4, 7]. The Ska complex contains multiple microtubule-binding elements and promotes kinetochore-microtubule attachment [8-11]. The Ska1 C-terminal domain (CTD) recruits protein phosphatase 1 (PP1) to kinetochores to promote timely anaphase onset [12]. The Ska complex regulates, and is regulated by, Aurora B [13]. Aurora B phosphorylates both Ska1 and Ska3 to inhibit the kinetochore localization of the Ska complex [14]...
May 22, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28478994/emerging-paradigms-of-g-protein-coupled-receptor-dephosphorylation
#16
REVIEW
Andrea Kliewer, Rainer K Reinscheid, Stefan Schulz
Elucidation of the molecular mechanisms underlying G protein-coupled receptor (GPCR) dephosphorylation remains a major challenge. While specific GPCR phosphatases (GRPs) have eluded identification, prevailing models propose that receptors must first internalize into acidic endosomes to become dephosphorylated in a housekeeping-like process. Recently, phosphosite-specific antibodies, combined with siRNAs targeting specific phosphatase transcripts, have facilitated the identification of distinct protein phosphatase 1 (PP1) and PP2 catalytic subunits as bona fide GRPs...
May 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28476946/in-vivo-calcium-signaling-during-synaptic-refinement-at-the-drosophila-neuromuscular-junction
#17
Fernando Vonhoff, Haig Keshishian
Neural activity plays a key role in pruning aberrant synapses in various neural systems, including the mammalian cortex, where low-frequency (0.01 Hz) calcium oscillations refine topographic maps. However, the activity-dependent molecular mechanisms remain incompletely understood. Activity-dependent pruning also occurs at embryonic Drosophila neuromuscular junctions (NMJs), where low-frequency Ca(2+) oscillations are required for synaptic refinement and the response to the muscle-derived chemorepellant Sema2a...
May 31, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28469640/tissue-type-plasminogen-activator-is-a-homeostatic-regulator-of-synaptic-function-in-the-central-nervous-system
#18
REVIEW
Valerie Jeanneret, Manuel Yepes
Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons. Once in the synaptic cleft this tPA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles, and regulates the postsynaptic response to the presynaptic release of glutamate. Indeed, tPA has a bidirectional effect on the composition of the postsynaptic density (PSD) that does not require plasmin generation or the presynaptic release of glutamate, but varies according to the baseline level of neuronal activity...
March 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28463114/protein-phosphatase-1-inactivates-mps1-to-ensure-efficient-spindle-assembly-checkpoint-silencing
#19
Margarida Moura, Mariana Osswald, Nelson Leça, João Barbosa, António J Pereira, Helder Maiato, Claudio E Sunkel, Carlos Conde
Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown...
May 2, 2017: ELife
https://www.readbyqxmd.com/read/28460125/how-protein-kinase-a-activates-canonical-tyrosine-kinase-signaling-pathways-to-promote-granulosa-cell-differentiation
#20
Nathan C Law, Elyse M Donaubauer, Anthony J Zeleznik, Mary Hunzicker-Dunn
Protein kinase A (PKA) has recently been shown to mimic the actions of follicle-stimulating hormone (FSH) by activating signaling pathways that promote granulosa cell (GC) differentiation, such as phosphatidylinositol 3-kinase (PI3K) and mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We sought to elucidate the mechanism by which PKA, a Ser/Thr kinase, intersected the PI3K/AKT and MAPK/ERK pathways that are canonically activated by receptor tyrosine kinases (RTKs). Our results show that for both of these pathways, the RTK is active in the absence of FSH yet signaling down the pathways to commence transcriptional responses requires FSH-stimulated PKA activation...
April 28, 2017: Endocrinology
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