scholarly journals A structural dynamics model for how CPEB3 binding to SUMO2 can regulate translational control in dendritic spines

2021 ◽  
Author(s):  
Xinyu Gu ◽  
Nicholas P. Schafer ◽  
Carlos Bueno ◽  
Wei Lu ◽  
Peter G. Wolynes
Keyword(s):  
Structural Dynamics ◽  
Dendritic Spines ◽  
Translational Control ◽  
Rna Binding ◽  
Complex Structure ◽  
Free Energy Calculations ◽  
Local Translation ◽  
Dynamics Model ◽  
Equilibrium Shift

A prion-like RNA-binding protein, CPEB3, can regulate local translation in dendritic spines. CPEB3 monomers repress translation, whereas CPEB3 aggregates activate translation of its target mRNAs. However, the CPEB3 aggregates, as long-lasting prions, may raise the problem of unregulated translational activation. Here, we propose a computational model of the complex structure between CPEB3 RNA-binding domain (CPEB3-RBD) and small ubiquitin-like modifier protein 2 (SUMO2). Free energy calculations suggest that the allosteric effect of CPEB3-RBD/SUMO2 interaction can amplify the RNA-binding affinity of CPEB3. Combining with previous experimental observations on the SUMOylation mode of CPEB3, this model suggests an equilibrium shift of mRNA from binding to deSUMOylated CPEB3 aggregates to binding to SUMOylated CPEB3 monomers in basal synapses. This work shows how a burst of local translation in synapses can be silenced following a stimulation pulse, and explores the CPEB3/SUMO2 interplay underlying the structural change of synapses and the formation of long-term memories.

scholarly journals Exploring the F-actin/CPEB3 interaction and its possible role in the molecular mechanism of long-term memory

2020 ◽  
Vol 117 (36) ◽  
pp. 22128-22134
Author(s):  
Xinyu Gu ◽  
Nicholas P. Schafer ◽  
Qian Wang ◽  
Sarah S. Song ◽  
Mingchen Chen ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Dendritic Spines ◽  
Molecular Model ◽  
Complex Structure ◽  
Long Term Memory ◽  
Term Memory ◽  
Input Signals ◽  
Cytoskeleton Remodeling ◽  
Beta Hairpin

Dendritic spines are tiny membranous protrusions on the dendrites of neurons. Dendritic spines change shape in response to input signals, thereby strengthening the connections between neurons. The growth and stabilization of dendritic spines is thought to be essential for maintaining long-term memory. Actin cytoskeleton remodeling in spines is a key element of their formation and growth. More speculatively, the aggregation of CPEB3, a functional prion that binds RNA, has been reported to be involved in the maintenance of long-term memory. Here we study the interaction between actin and CPEB3 and propose a molecular model for the complex structure of CPEB3 and an actin filament (F-actin). The results of our computational modeling, including both energetic and structural analyses, are compared with novel data from peptide array experiments. Our model of the CPEB3/F-actin interaction suggests that F-actin potentially triggers the aggregation-prone structural transition of a short CPEB3 sequence by zipping it into a beta-hairpin form. We also propose that the CPEB3/F-actin interaction might be regulated by the SUMOylation of CPEB3, based on bioinformatic searches for potential SUMOylation sites as well as SUMO interacting motifs in CPEB3. On the basis of these results and the existing literature, we put forward a possible molecular mechanism underlying long-term memory that involves CPEB3’s binding to actin, its aggregation, and its regulation by SUMOylation.

scholarly journals Vectorial Channeling as a Mechanism for Translational Control by Functional Prions and Condensates

2021 ◽  
Author(s):  
Xinyu Gu ◽  
Nicholas P Schafer ◽  
Peter G Wolynes
Keyword(s):  
Experimental Data ◽  
Dendritic Spines ◽  
Translational Control ◽  
Messenger Rna ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Potential Of Mean Force ◽  
Translation Control ◽  
Through Diffusion

Translation of messenger RNA is regulated through a diverse set of RNA-binding proteins. A significant fraction of RNA-binding proteins contain prion-like domains which form functional prions. This raises the question of how prions can play a role in translational control. Local control of translation in dendritic spines by prions has been invoked in the mechanism of synaptic plasticity and memory. We show how channeling through diffusion and processive translation cooperate in highly ordered mRNA/prion aggregates as well as in less ordered mRNA/protein condensates depending on their substructure. We show the direction of translational control, whether it is repressive or activating, depends on the polarity of the mRNA distribution in mRNA/prion assemblies which determines whether vectorial channeling can enhance recycling of ribosomes. Our model also addresses the effect of changes of substrate concentration in assemblies that have been suggested previously to explain translation control by assemblies through the introduction of a potential of mean force biasing diffusion of ribosomes inside the assemblies. The results from the model are compared with the experimental data on translational control by two functional RNA-binding prions, CPEB involved in memory and Rim4 involved in gametogenesis.

scholarly journals Staufen1 Regulation of Protein Synthesis-Dependent Long-Term Potentiation and Synaptic Function in Hippocampal Pyramidal Cells

2008 ◽  
Vol 28 (9) ◽  
pp. 2896-2907 ◽  
Author(s):  
Geneviève Lebeau ◽  
Marjolaine Maher-Laporte ◽  
Lisa Topolnik ◽  
Charles E. Laurent ◽  
Wayne Sossin ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Translational Control ◽  
Rna Binding ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Down Regulation ◽  
Spine Shape ◽  
Term Potentiation

ABSTRACT Staufen1 (Stau1) is an RNA-binding protein involved in transport, localization, decay, and translational control of mRNA. In neurons, it is present in cell bodies and also in RNA granules which are transported along dendrites. Dendritic mRNA localization might be involved in long-term synaptic plasticity and memory. To determine the role of Stau1 in synaptic function, we examined the effects of Stau1 down-regulation in hippocampal slice cultures using small interfering RNA (siRNA). Biolistic transfection of Stau1 siRNA resulted in selective down-regulation of Stau1 in slice cultures. Consistent with a role of Stau1 in transporting mRNAs required for synaptic plasticity, Stau1 down-regulation impaired the late form of chemically induced long-term potentiation (L-LTP) without affecting early-LTP, mGluR1/5-mediated long-term depression, or basal evoked synaptic transmission. Stau1 down-regulation decreased the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting a role in maintaining efficacy at hippocampal synapses. At the cellular level, Stau1 down-regulation shifted spine shape from regular to elongated spines, without changes in spine density. The change in spine shape could be rescued by an RNA interference-resistant Stau1 isoform. Therefore, Stau1 is important for processing and/or transporting in dendrites mRNAs that are critical in regulation of synaptic strength and maintenance of functional connectivity changes underlying hippocampus-dependent learning and memory.

scholarly journals Vectorial channeling as a mechanism for translational control by functional prions and condensates

2021 ◽  
Vol 118 (47) ◽  
pp. e2115904118
Author(s):  
Xinyu Gu ◽  
Nicholas P. Schafer ◽  
Peter G. Wolynes
Keyword(s):  
Experimental Data ◽  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Translational Control ◽  
Messenger Rna ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Potential Of Mean Force ◽  
Through Diffusion

Translation of messenger RNA (mRNA) is regulated through a diverse set of RNA-binding proteins. A significant fraction of RNA-binding proteins contains prion-like domains which form functional prions. This raises the question of how prions can play a role in translational control. Local control of translation in dendritic spines by prions has been invoked in the mechanism of synaptic plasticity and memory. We show how channeling through diffusion and processive translation cooperate in highly ordered mRNA/prion aggregates as well as in less ordered mRNA/protein condensates depending on their substructure. We show that the direction of translational control, whether it is repressive or activating, depends on the polarity of the mRNA distribution in mRNA/prion assemblies which determines whether vectorial channeling can enhance recycling of ribosomes. Our model also addresses the effect of changes of substrate concentration in assemblies that have been suggested previously to explain translational control by assemblies through the introduction of a potential of mean force biasing diffusion of ribosomes inside the assemblies. The results from the model are compared with the experimental data on translational control by two functional RNA-binding prions, CPEB involved in memory and Rim4 involved in gametogenesis.

scholarly journals Transforming a Liability into an Asset: A System Dynamics Model for Free-Ranging Dog Population Management

Systems ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 56
Author(s):  
Urmila Basu Mallick ◽  
Marja H. Bakermans ◽  
Khalid Saeed
Keyword(s):  
System Dynamics ◽  
Social Integration ◽  
Unintended Consequences ◽  
System Dynamics Model ◽  
Dynamics Model ◽  
Innovative Strategies ◽  
Management Context ◽  
Free Ranging ◽  
Social Rewards

Using Indian free-ranging dogs (FRD) as a case study, we propose a novel intervention of social integration alongside previously proposed methods for dealing with FRD populations. Our study subsumes population dynamics, funding avenues, and innovative strategies to maintain FRD welfare and provide societal benefits. We develop a comprehensive system dynamics model, featuring identifiable parameters customizable for any management context and imperative for successfully planning a widescale FRD population intervention. We examine policy resistance and simulate conventional interventions alongside the proposed social integration effort to compare monetary and social rewards, as well as costs and unintended consequences. For challenging socioeconomic ecological contexts, policy resistance is best overcome by shifting priority strategically between social integration and conventional techniques. The results suggest that social integration can financially support a long-term FRD intervention, while transforming a “pest” population into a resource for animal-assisted health interventions, law enforcement, and conservation efforts.

Removal of a compressive mass causes a transient disruption of blood-brain barrier but a long-term recovery of spiny stellate neurons in the rat somatosensory cortex

2021 ◽  
pp. 1-17
Author(s):  
Tzu-Yin Yeh ◽  
Pei-Hsin Liu
Keyword(s):  
Somatosensory Cortex ◽  
Blood Brain Barrier ◽  
Dendritic Spines ◽  
Late Onset ◽  
Brain Barrier ◽  
Blood Brain ◽  
Afferent Fibers ◽  
Prolonged Recovery ◽  
Rat Somatosensory Cortex

Background: In the cranial cavity, a space-occupying mass such as epidural hematoma usually leads to compression of brain. Removal of a large compressive mass under the cranial vault is critical to the patients. Objective: The purpose of this study was to examine whether and to what extent epidural decompression of the rat primary somatosensory cortex affects the underlying microvessels, spiny stellate neurons and their afferent fibers. Methods: Rats received epidural decompression with preceding 1-week compression by implantation of a bead. The thickness of cortex was measured using brain coronal sections. The permeability of blood-brain barrier (BBB) was assessed by Evans Blue and immunoglobulin G extravasation. The dendrites and dendritic spines of the spiny stellate neurons were revealed by Golgi— Cox staining and analyzed. In addition, the thalamocortical afferent (TCA) fibers in the cortex were illustrated using anterograde tracing and examined. Results: The cortex gradually regained its thickness over time and became comparable to the sham group at 3 days after decompression. Although the diameter of cortical microvessels were unaltered, a transient disruption of the BBB was observed at 6 hours and 1 day after decompression. Nevertheless, no brain edema was detected. In contrast, the dendrites and dendritic spines of the spiny stellate neurons and the TCA fibers were markedly restored from 2 weeks to 3 months after decompression. Conclusions: Epidural decompression caused a breakdown of the BBB, which was early-occurring and short-lasting. In contrast, epidural decompression facilitated a late-onset and prolonged recovery of the spiny stellate neurons and their afferent fibers.

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