scholarly journals Activity-regulated synaptic targeting of lncRNA ADEPTR mediates structural plasticity by localizing Sptn1 and AnkB in dendrites

2021 ◽  
Vol 7 (16) ◽  
pp. eabf0605
Author(s):  
Eddie Grinman ◽  
Yoshihisa Nakahata ◽  
Yosef Avchalumov ◽  
Isabel Espadas ◽  
Supriya Swarnkar ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Noncoding Rna ◽  
Molecular Motor ◽  
Structural Plasticity ◽  
Dependent Manner ◽  
Protein Coding ◽  
Synaptic Targeting ◽  
Conserved Sequence ◽  
Activity Dependent

Activity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long noncoding transcriptome remains elusive. Here, we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—that is up-regulated and synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independently of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators ankyrin (AnkB) and spectrin (Sptn1) via a conserved sequence and is required for their dendritic localization. Together, this study demonstrates how activity-dependent synaptic targeting of an lncRNA mediates structural plasticity at the synapse.

scholarly journals A cAMP/PKA-dependent synaptically targeted lncRNA mediates structural plasticity in hippocampal neurons by functionally interacting with the Spectrin/Ankyrin Network

2020 ◽  
Author(s):  
Eddie Grinman ◽  
Yoshihisa Nakahata ◽  
Yosef Avchalumov ◽  
Isabel Espadas ◽  
Supriya Swarnkar ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Long Noncoding Rna ◽  
Hippocampal Neurons ◽  
Noncoding Rna ◽  
Molecular Motor ◽  
Structural Plasticity ◽  
Dependent Manner ◽  
Protein Coding ◽  
Activity Dependent

AbstractActivity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long-noncoding transcriptome remains elusive. Here we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—whose expression is upregulated and is synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independent of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators Ankyrin (AnkB) and Spectrin (Sptn1) and is required for their dendritic localization. Taken together, this study demonstrates that ADEPTR regulates the dendritic Spectrin-Ankyrin network for structural plasticity at the synapse and illuminates a novel role for lncRNAs at the synapse.One Sentence SummaryWe have uncovered an intronic long noncoding RNA that is synaptically transported in a cAMP-dependent manner and is linked to cytoskeletal components of structural plasticity in hippocampal neurons.

scholarly journals Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer

2020 ◽  
Vol 6 (3) ◽  
pp. 27 ◽  
Author(s):  
Dominik A. Barth ◽  
Felix Prinz ◽  
Julia Teppan ◽  
Katharina Jonas ◽  
Christiane Klec ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Protein Coding ◽  
Rna Molecules ◽  
Von Hippel Lindau ◽  
Hypoxic Conditions ◽  
Main Regulator ◽  
Upstream Regulators

Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.

scholarly journals Metformin Alleviated Aβ-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Bin Chen ◽  
Ying Teng ◽  
Xingguang Zhang ◽  
Xiaofeng Lv ◽  
Yanling Yin
Keyword(s):  
P38 Mapk ◽  
Hippocampal Neurons ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ldh Assay ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Positive Effect

Both diabetes and hyperinsulinemia are confirmed risk factors for Alzheimer’s disease. Some researchers proposed that antidiabetic drugs may be used as disease-modifying therapies, such as metformin and thiazolidinediones, although more evidence was poorly supported. The aim of the current study is to investigate the role of metformin in Aβ-induced cytotoxicity and explore the underlying mechanisms. First, the experimental results show that metformin salvaged the neurons exposed to Aβin a concentration-dependent manner with MTT and LDH assay. Further, the phosphorylation levels of JNK, ERK1/2, and p38 MAPK were measured with western blot analysis. It was investigated that Aβincreased phospho-JNK significantly but had no effect on phospho-p38 MAPK and phospho-ERK1/2. Metformin decreased hyperphosphorylated JNK induced by Aβ; however, the protection of metformin against Aβwas blocked when anisomycin, the activator of JNK, was added to the medium, indicating that metformin performed its protection against Aβin a JNK-dependent way. In addition, it was observed that metformin protected the neurons via the suppression of apoptosis. Taken together, our findings demonstrate that metformin may have a positive effect on Aβ-induced cytotoxicity, which provides a preclinical strategy against AD for elders with diabetes.

scholarly journals TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Valerie T. Ramírez ◽  
Eva Ramos-Fernández ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Protein Kinase ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Biological Effects ◽  
Critical Role ◽  
Head Width ◽  
Dependent Manner ◽  
Spine Density ◽  
Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

scholarly journals The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Keimpe D. B. Wierda ◽  
Trine L. Toft-Bertelsen ◽  
Casper R. Gøtzsche ◽  
Ellis Pedersen ◽  
Irina Korshunova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Prolonged Exposure ◽  
Calcium Influx ◽  
Dependent Manner ◽  
Cellular Effects ◽  
Glutamatergic Neurons ◽  
Readily Releasable Pool ◽  
Presynaptic Release ◽  
Activity Dependent

Abstract Classically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.

scholarly journals Role of long noncoding RNA taurine‐upregulated gene 1 in cancers

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Miao Da ◽  
Jing Zhuang ◽  
Yani Zhou ◽  
Quan Qi ◽  
Shuwen Han
Keyword(s):  
Noncoding Rna ◽  
Cancer Cell Proliferation ◽  
Research Directions ◽  
Protein Coding ◽  
Clinical Biomarker ◽  
Non Coding Rnas ◽  
New Research ◽  
Taurine Upregulated Gene 1 ◽  
Competitive Endogenous Rna

AbstractLong non-coding RNAs (lncRNAs) are a group of non-protein coding RNAs with a length of more than 200 bp. The lncRNA taurine up-regulated gene 1 (TUG1) is abnormally expressed in many human malignant cancers, where it acts as a competitive endogenous RNA (ceRNA), regulating gene expression by specifically sponging its corresponding microRNAs. In the present review, we summarised the current understanding of the role of lncRNA TUG1 in cancer cell proliferation, metastasis, angiogenesis, chemotherapeutic drug resistance, radiosensitivity, cell regulation, and cell glycolysis, as well as highlighting its potential application as a clinical biomarker or therapeutic target for malignant cancer. This review provides the basis for new research directions for lncRNA TUG1 in cancer prevention, diagnosis, and treatment.

scholarly journals A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association

2020 ◽  
Vol 48 (21) ◽  
pp. 12116-12134
Author(s):  
Mengmeng Han ◽  
Jialun Li ◽  
Yaqiang Cao ◽  
Yuanyong Huang ◽  
Wen Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Replication Fork ◽  
De Novo ◽  
Embryonic Stem ◽  
Dna Helicase ◽  
Dependent Manner ◽  
Essential Factor ◽  
Activity Dependent ◽  
Insight Into

Abstract LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.

scholarly journals Interleukin-1 Mediates Induction of Tolerance to Global Ischemia in Gerbil Hippocampal CA1 Neurons

1996 ◽  
Vol 16 (6) ◽  
pp. 1137-1142 ◽  
Author(s):  
Toshiho Ohtsuki ◽  
Christi A. Ruetzler ◽  
Kaoru Tasaki ◽  
John M. Hallenbeck
Keyword(s):  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Interleukin 1 ◽  
Tolerance Induction ◽  
Global Ischemia ◽  
Mongolian Gerbils ◽  
Dependent Manner ◽  
Group I ◽  
Induction Of Tolerance

A series of experiments was performed to determine the role of interleukin (IL)-1 in the induction of tolerance to global ischemia in Mongolian gerbils. In Group I, a 2-min “preconditioning” ischemia protected CA1 hippocampal neurons in gerbils subjected to 3.5 min ischemia 3 days later. CA1 neuronal density was: sham, 171 ± 3/mm; 3.5 min ischemia, 30 ± 30/mm; 2 and 3.5 min ischemia 162 ± 6/mm. Experiments in Group II addressed the role of IL-1 in the induction of tolerance by sublethal ischemia. Arterial IL-1α and IL-Iβ became elevated between 1 and 3 days after a 2-min ischemic exposure. IL-1α was: sham, 6.4 ± 0.6 ng/ml; and 2-day, 10.2 ± 1.2 ng/ml. IL-1β was: sham, 6.4 ± 0.5 ng/ml; and 2-day, 17.3 ± 2 ng/ml. Recombinant human IL-1 receptor antagonist (IL-1ra) i.p. blocked ischemic tolerance induction by 2-min preconditioning ischemia: 2-min ischemia + vehicle, 162 ± 6/mm; and 2-min ischemia + IL-1ra, 67 ± 17/mm. Experiments in Group III assessed the capacity of IL-1 to induce tolerance to brain ischemia. IL-1α i.p. (0, 10, 20 μg/kg) for 3 days prior to 3.5-min forebrain ischemia provided significant CA1 neuroprotection in a dose-dependent manner: 2 ± 2, 68 ± 83, and 129 ± 42/mm, respectively. IL-1β (15 μg/kg) in combination with either IL-1ra (100 mg/kg) or IL-1ra vehicle i.p. on the same schedule demonstrated a significant CA1 neuroprotection that could be nullified by IL-1ra: IL-1β + IL-1ra vehicle, 153 ± 16/mm; and IL-1β + IL-1ra, 67 ± 36/mm. Recognition that tolerance arises from stimulation of a known receptor (IL-1RI) permits molecular analysis of the intracellular signaling that is critical for production of that state.

scholarly journals Secretory phospholipases A2 induce neurite outgrowth in PC12 cells

2003 ◽  
Vol 376 (3) ◽  
pp. 655-666 ◽  
Author(s):  
Satoru NAKASHIMA ◽  
Yutaka IKENO ◽  
Tatsuya YOKOYAMA ◽  
Masakazu KUWANA ◽  
Angelo BOLCHI ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Streptomyces Coelicolor ◽  
Dependent Manner ◽  
Group V ◽  
Phospholipases A2 ◽  
Fatty Acid Release ◽  
Activity Dependent

sPLA2s (secretory phospholipases A2) belong to a broad and structurally diverse family of enzymes that hydrolyse the sn-2 ester bond of glycerophospholipids. We previously showed that a secreted fungal 15 kDa protein, named p15, as well as its orthologue from Streptomyces coelicolor (named Scp15) induce neurite outgrowth in PC12 cells at nanomolar concentrations. We report here that both p15 and Scp15 are members of a newly identified group of fungal/bacterial sPLA2s. The phospholipid-hydrolysing activity of p15 is absolutely required for neurite outgrowth induction. Mutants with a reduced PLA2 activity exhibited a comparable reduction in neurite-inducing activity, and the ability to induce neurites closely matched the capacity of various p15 forms to promote fatty acid release from live PC12 cells. A structurally divergent member of the sPLA2 family, bee venom sPLA2, also induced neurites in a phospholipase activity-dependent manner, and the same effect was elicited by mouse group V and X sPLA2s, but not by group IB and IIA sPLA2s. Lysophosphatidylcholine, but not other lysophospholipids, nor arachidonic acid, elicited neurite outgrowth in an L-type Ca2+ channel activity-dependent manner. In addition, p15-induced neuritogenesis was unaffected by various inhibitors that block arachidonic acid conversion into bioactive eicosanoids. Altogether, these results delineate a novel, Ca2+- and lysophosphatidylcholine-dependent neurotrophin-like role of sPLA2s in the nervous system.

PROBABILITY OF ENTRAINMENT, SYNAPTIC MODIFICATION AND ENTRAINED PHASE ARE PHASE-DEPENDENT IN STDP

2010 ◽  
Vol 18 (02) ◽  
pp. 479-493
Author(s):  
GANG ZHAO
Keyword(s):  
Neural Coding ◽  
Numerical Study ◽  
Spike Timing ◽  
Dependent Manner ◽  
Initial State ◽  
Pacemaker Neurons ◽  
Strongly Nonlinear ◽  
Synaptic Modification ◽  
Activity Dependent

Synaptic conductance can be modified in an activity dependent manner, in which the temporal relationship between pre- and post-synaptic spikes plays a major role. This spike timing dependent plasticity (STDP) has profound implications in neural coding, computation and functionality. Because the STDP learning curve is strongly nonlinear, initial state may have great impacts on the eventual state of the system. However, although this feature is intuitively clear, it has not been explored in detail before. This paper presents a preliminary numerical study in this direction. In a model of two pacemaker neurons and a synapse undergoing STDP, it is found that the probability of entrainment, direction of synaptic modification and entrained phase are all influenced by the initial relative phase. Based on these findings, it is reasonable to propose that the initial-state sensitive feature of STDP may contribute to its role of selective response in oscillatory neural networks.

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