scholarly journals GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior

2019 ◽  
Vol 5 (4) ◽  
pp. eaau8237 ◽  
Author(s):  
Kelvin K. Hui ◽  
Noriko Takashima ◽  
Akiko Watanabe ◽  
Thomas E. Chater ◽  
Hiroshi Matsukawa ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Physiological Role ◽  
Neuropsychiatric Disorders ◽  
Receptor Trafficking ◽  
Gabaergic Interneurons ◽  
Potential Mechanism ◽  
Behavioral Deficits ◽  
Receptor Associated Protein ◽  
High Molecular Weight Species ◽  
Functional Analyses

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor–associated protein-like 2 (GABARAPL2) to differentially form high–molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

scholarly journals The Physiological Roles of Vitamin E and Hypovitaminosis E in the Transition Period of High-Yielding Dairy Cows

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1088
Author(s):  
Satoshi Haga ◽  
Hiroshi Ishizaki ◽  
Sanggun Roh
Keyword(s):  
Dairy Cows ◽  
High Performance ◽  
Molecular Mechanisms ◽  
Transition Period ◽  
Disease Risk ◽  
Serum Vitamin ◽  
Physiological Role ◽  
Density Lipoprotein ◽  
Alpha Tocopherol ◽  
Transition Dairy Cows

Levels of alpha-tocopherol (α-Toc) decline gradually in blood throughout prepartum, reaching lowest levels (hypovitaminosis E) around calving. Despite numerous reports about the disease risk in hypovitaminosis E and the effect of α-Toc supplementation on the health of transition dairy cows, its risk and supplemental effects are controversial. Here, we present some novel data about the disease risk of hypovitaminosis E and the effects of α-Toc supplementation in transition dairy cows. These data strongly demonstrate that hypovitaminosis E is a risk factor for the occurrence of peripartum disease. Furthermore, a study on the effectiveness of using serum vitamin levels as biomarkers to predict disease in dairy cows was reported, and a rapid field test for measuring vitamin levels was developed. By contrast, evidence for how hypovitaminosis E occurred during the transition period was scarce until the 2010s. Pioneering studies conducted with humans and rodents have identified and characterised some α-Toc-related proteins, molecular players involved in α-Toc regulation followed by a study in ruminants from the 2010s. Based on recent literature, the six physiological factors: (1) the decline in α-Toc intake from the close-up period; (2) changes in the digestive and absorptive functions of α-Toc; (3) the decline in plasma high-density lipoprotein as an α-Toc carrier; (4) increasing oxidative stress and consumption of α-Toc; (5) decreasing hepatic α-Toc transfer to circulation; and (6) increasing mammary α-Toc transfer from blood to colostrum, may be involved in α-Toc deficiency during the transition period. However, the mechanisms and pathways are poorly understood, and further studies are needed to understand the physiological role of α-Toc-related molecules in cattle. Understanding the molecular mechanisms underlying hypovitaminosis E will contribute to the prevention of peripartum disease and high performance in dairy cows.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Serial analysis of gene expression (SAGE) during porcine embryo development

2004 ◽  
Vol 16 (2) ◽  
pp. 87 ◽  
Author(s):  
Le Ann Blomberg ◽  
Kurt A. Zuelke
Keyword(s):  
Gene Expression ◽  
Functional Genomics ◽  
Embryo Development ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Transgenic Animals ◽  
Specific Gene ◽  
Research Strategies

Functional genomics provides a powerful means for delving into the molecular mechanisms involved in pre-implantation development of porcine embryos. High rates of embryonic mortality (30%), following either natural mating or artificial insemination, emphasise the need to improve the efficiency of reproduction in the pig. The poor success rate of live offspring from in vitro-manipulated pig embryos also hampers efforts to generate transgenic animals for biotechnology applications. Previous analysis of differential gene expression has demonstrated stage-specific gene expression for in vivo-derived embryos and altered gene expression for in vitro-derived embryos. However, the methods used to date examine relatively few genes simultaneously and, thus, provide an incomplete glimpse of the physiological role of these genes during embryogenesis. The present review will focus on two aspects of applying functional genomics research strategies for analysing the expression of genes during elongation of pig embryos between gestational day (D) 11 and D12. First, we compare and contrast current methodologies that are being used for gene discovery and expression analysis during pig embryo development. Second, we establish a paradigm for applying serial analysis of gene expression as a functional genomics tool to obtain preliminary information essential for discovering the physiological mechanisms by which distinct embryonic phenotypes are derived.

scholarly journals Gene Expressing and sRNA Sequencing Show That Gene Differentiation Associates with a YellowAcer palmatumMutant Leaf in Different Light Conditions

2015 ◽  
Vol 2015 ◽  
pp. 1-10
Author(s):  
Shu-Shun Li ◽  
Qian-Zhong Li ◽  
Li-Ping Rong ◽  
Ling Tang ◽  
Bo Zhang
Keyword(s):  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Light Condition ◽  
Low Density ◽  
Physiological Changes ◽  
Potential Mechanism ◽  
Light Conditions ◽  
Pigment Synthesis ◽  
Leaf Coloration ◽  
Gene Expressing

Acer palmatumThunb., like other maples, is a widely ornamental-use small woody tree for leaf shapes and colors. Interestingly, we found a yellow-leaves mutant “Jingling Huangfeng” turned to green when grown in shade or low-density light condition. In order to study the potential mechanism, we performed high-throughput sequencing and obtained 1,082 DEGs in leaves grown in different light conditions that result inA. palmatumsignificant morphological and physiological changes. A total of 989 DEGs were annotated and clustered, of which many DEGs were found associating with the photosynthesis activity and pigment synthesis. The expression of CHS and FDR gene was higher while the expression of FLS gene was lower in full-sunlight condition; this may cause more colorful substance like chalcone and anthocyanin that were produced in full-light condition, thus turning the foliage to yellow. Moreover, this is the first available miRNA collection which contains 67 miRNAs ofA. palmatum, including 46 conserved miRNAs and 21 novel miRNAs. To get better understanding of which pathways these miRNAs involved, 102 Unigenes were found to be potential targets of them. These results will provide valuable genetic resources for further study on the molecular mechanisms ofAcer palmatumleaf coloration.

Insulin receptors: binding kinetics and structure-function relationship of insulin

1984 ◽  
Vol 64 (4) ◽  
pp. 1321-1378 ◽  
Author(s):  
S. Gammeltoft
Keyword(s):  
Plasma Membrane ◽  
Binding Affinity ◽  
Insulin Action ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Insulin Receptors ◽  
Binding Kinetics ◽  
Antigenic Determinants ◽  
Insulin Degradation ◽  
Recent Advances

During the last decade, earlier suggestions that insulin acts at the plasma membrane level via combination with receptors have been amply confirmed in studies of 125I-labeled insulin binding kinetics. Efforts have been devoted to the development of homogeneous, stable, and bioactive tracers, and a preparation of monoiodo[TyrA14]insulin showed 100-125% biological activity. The initially simple model of reversible, bimolecular, and noncooperative interaction between receptor and insulin has been revised to include the existence of at least three affinity states that may be linked to modulation of the biological response induced by the insulin-receptor complex. Thus negative cooperativity seems important in reducing oscillations of insulin action with variations in plasma insulin concentration, and formation of a high-affinity state or positive cooperativity may lead to desensitization of receptors. The kinetic phenomena suggest that receptor-binding affinity and function are actively regulated by insulin itself. At present the receptor model is purely functional and does not imply molecular mechanisms. However, recent advances in the analysis of receptor structure and biochemistry promise that the molecular equivalents of the kinetic phenomena may be elucidated in the near future. Furthermore the reaction between receptor and insulin is irreversible because of degradation of receptor-bound insulin, which may result in termination of the metabolic activation. Morphological and biochemical work suggests that internalization of the receptor-insulin complex from the plasma membrane transfers insulin to intracellular organelles like the lysosomes, the Golgi apparatus, or nucleus, where degradation by insulin protease takes place, whereas the receptor is recycled back to the membrane. Recent advances in the studies of biosynthesis and cellular dynamics of receptors indicate that intracellular processing and redistribution of binding sites may play a role in the mechanism of insulin action. Insulin receptors are widely distributed in all cell types, but evidence has accumulated that receptors show tissue and species variations in their functional properties regarding binding affinity, insulin specificity, cooperativity, and insulin degradation and in structural properties such as antigenic determinants and glycosidic composition. Perhaps these differences reflect cellular adaptations and variations in the physiological role of insulin.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-28 ◽  
Author(s):  
Fiona Limanaqi ◽  
Stefano Gambardella ◽  
Francesca Biagioni ◽  
Carla L. Busceti ◽  
Francesco Fornai
Keyword(s):  
Molecular Mechanisms ◽  
Neuropsychiatric Disorders ◽  
Behavioral Alterations ◽  
Neuronal Phenotype ◽  
Cellular Events ◽  
Epigenetic Effects ◽  
Molecular Events ◽  
Epigenetic Events ◽  
Genetic Modifications ◽  
Altered Gene

Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Understanding methamphetamine toxicity is key beyond the field of drug abuse since it allows getting an insight into the molecular mechanisms which operate in a variety of neuropsychiatric disorders. In fact, key alterations produced by methamphetamine involve dopamine neurotransmission in a way, which is reminiscent of spontaneous neurodegeneration and psychiatric schizophrenia. Thus, understanding the molecular mechanisms operated by methamphetamine represents a wide window to understand both the addicted brain and a variety of neuropsychiatric disorders. This overlapping, which is already present when looking at the molecular and cellular events promoted immediately after methamphetamine intake, becomes impressive when plastic changes induced in the brain of methamphetamine-addicted patients are considered. Thus, the present manuscript is an attempt to encompass all the molecular events starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons to explain how specific neurotransmitters and signaling cascades produce persistent genetic modifications, which shift neuronal phenotype and induce behavioral alterations. A special emphasis is posed on disclosing those early and delayed molecular events, which translate an altered neurotransmitter function into epigenetic events, which are derived from the translation of postsynaptic noncanonical signaling into altered gene regulation. All epigenetic effects are considered in light of their persistent changes induced in the postsynaptic neurons including sensitization and desensitization, priming, and shift of neuronal phenotype.

scholarly journals The collagen receptor uPARAP/Endo180 regulates collectins through unique structural elements in its FNII domain

2020 ◽  
Vol 295 (27) ◽  
pp. 9157-9170 ◽  
Author(s):  
Kirstine Sandal Nørregaard ◽  
Oliver Krigslund ◽  
Niels Behrendt ◽  
Lars H. Engelholm ◽  
Henrik Jessen Jürgensen
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Mannose Receptor ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Cellular Regulation ◽  
Urokinase Plasminogen Activator Receptor ◽  
Receptor Associated Protein ◽  
Additional Level ◽  
Collagen Receptor

C-type lectins that contain collagen-like domains are known as collectins. These proteins are present both in the circulation and in extravascular compartments and are central players of the innate immune system, contributing to first-line defenses against viral, bacterial, and fungal pathogens. The collectins mannose-binding lectin (MBL) and surfactant protein D (SP-D) are regulated by tissue fibroblasts at extravascular sites via an endocytic mechanism governed by urokinase plasminogen activator receptor–associated protein (uPARAP or Endo180), which is also a collagen receptor. Here, we investigated the molecular mechanisms that drive the uPARAP-mediated cellular uptake of MBL and SP-D. We found that the uptake depends on residues within a protruding loop in the fibronectin type-II (FNII) domain of uPARAP that are also critical for collagen uptake. Importantly, however, we also identified FNII domain residues having an exclusive role in collectin uptake. We noted that these residues are absent in the related collagen receptor, the mannose receptor (MR or CD206), which consistently does not interact with collectins. We also show that the second C-type lectin-like domain (CTLD2) is critical for the uptake of SP-D, but not MBL, indicating an additional level of complexity in the interactions between collectins and uPARAP. Finally, we demonstrate that the same molecular mechanisms enable uPARAP to engage MBL immobilized on the surface of pathogens, thereby expanding the potential biological implications of this interaction. Our study reveals molecular details of the receptor-mediated cellular regulation of collectins and offers critical clues for future investigations into collectin biology and pathology.

Clinically Relevant Concentrations of Propofol but Not Midazolam Alter In Vitro  Dendritic Development of Isolated γ-Aminobutyric Acid-positive Interneurons

2005 ◽  
Vol 102 (5) ◽  
pp. 970-976 ◽  
Author(s):  
Laszlo Vutskits ◽  
Eduardo Gascon ◽  
Edomer Tassonyi ◽  
Jozsef Zoltan Kiss
Keyword(s):  
Cell Death ◽  
Dendritic Growth ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Nervous System Development ◽  
Gabaergic Neurons ◽  
Aminobutyric Acid ◽  
Gabaergic Interneurons ◽  
Short Term Exposure ◽  
Dendritic Development

Background Recent laboratory studies showed that exposure to supraclinical concentrations of propofol can induce cell death of immature neurons. However, no data are available regarding the effects of clinically relevant concentrations of this agent on neuronal development. The authors addressed this issue by evaluating the effect of propofol on dendritic growth and arbor expansion of developing gamma-aminobutyric acid-positive (GABAergic) interneurons. Methods Immature neuroblasts were isolated from the newborn rat subventricular zone and differentiated into GABAergic interneurons in culture. In addition to cell death, the effects of increasing concentrations and durations of propofol exposure on neuronal dendritic development were evaluated using the following morphologic parameters: total dendritic length, primary dendrites, branching point, and Scholl analysis. Results The authors demonstrate that propofol induced cell death of GABAergic neurons at concentrations of 50 microg/ml or greater. As little as 1 microg/ml propofol significantly altered several aspects of dendritic development, and as little as 4 h of exposure to this agent resulted in a persistent decrease in dendritic growth. In contrast, application of midazolam did not affect neuronal development. Conclusion Short-term exposure of immature developing GABAergic neurons to clinically relevant concentrations of propofol can induce long-term changes in dendritic arbor development. These results suggest that propofol anesthesia during central nervous system development could interfere with the molecular mechanisms driving the differentiation of GABAergic neurons and thus could potentially lead to impairment of neural networks.

scholarly journals LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

2020 ◽  
Vol 12 (565) ◽  
pp. eaay0399
Author(s):  
Changyoun Kim ◽  
Alexandria Beilina ◽  
Nathan Smith ◽  
Yan Li ◽  
Minhyung Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Activated T Cells ◽  
Behavioral Deficits ◽  
Downstream Signaling ◽  
Toll Like Receptor 2 ◽  
Factor Α

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein–mediated microglial neurotoxicity via lowering of tumor necrosis factor–α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

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