scholarly journals Amyloid conformers of the FXR1 protein prevent mRNA degradation in cortical neurons

2019 ◽  
Author(s):  
J.V. Sopova ◽  
E. I Koshel ◽  
T.A. Belashova ◽  
S.P. Zadorsky ◽  
A.V. Sergeeva ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Large Scale ◽  
Amyloid Fibrils ◽  
Mammalian Species ◽  
Rnase A ◽  
Mammalian Brain ◽  
Polarization Microscopy ◽  
Proteomic Approach ◽  
Functional Amyloids

AbstractFunctional amyloids regulate vital processes in a variety of organisms from bacteria to higher eukaryotes. The development of methods enabling large-scale screening for amyloids opens up opportunity for systemic analysis of the prevalence of amyloids in nature. Using an original proteomic approach, we identified several proteins forming amyloid-like detergent-resistant aggregates in the rat brain. One of them is the FXR1 protein, which is known to regulate memory and emotions (1, 2). We demonstrated that in brain FXR1 forms amyloid oligomers and insoluble detergent-resistant aggregates that strongly colocalize with amyloid-specific dye Thioflavin S and bind mRNA molecules. Moreover, we demonstrated that mRNAs colocalized with FXR1 amyloid particles are completely resistant to treatment with RNAse A. Taking into consideration that the members of ribonuclease A superfamily function in neurons (3) we can conclude that amyloid conformers of FXR1 control RNA stability in brain. Thus, in contrast to pathological amyloids that cause neurodegeneration, FXR1 is the functional amyloid in forebrain. We showed that amyloid properties of FXR1 depend on its N-terminal part from 1 to 379 amino acids. This fragment forms amyloid fibrils in vitro that bind Congo red and manifest apple-green birefringence when assayed by polarization microscopy. The amyloid-forming region of FXR1 is highly conserved in mammals. These data suggest that the ability of amyloid conformers of FXR1 to protect mRNAs is characteristic of different mammalian species, including humans.Significance StatementAmyloids are highly ordered cross-β sheet protein fibrils associated with many neurodegenerative diseases including Alzheimer’s disease. However, some amyloid proteins regulate vital processes. We identified a set of proteins that form amyloid-like aggregates in the brain of healthy rats. One of them - the FXR1 protein is known to regulate memory and emotions. FXR1 forms amyloid fibrils that bind RNA molecules and prevent their degradation in brain cortex neurons. Amyloid-forming sequence of FXR1 is highly conserved across mammals including human. Discovery of functional amyloids in mammalian brain shows that strategy aimed at the development of universal anti-amyloid drugs is unpromising. Such potential drugs should prevent or suppress formation of pathological aggregates of a certain protein, but not affect functional amyloids.

scholarly journals Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

2021 ◽  
Author(s):  
E. Stroo ◽  
L. Janssen ◽  
O. Sin ◽  
W. Hogewerf ◽  
M. Koster ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Fibrils ◽  
Mammalian Brain ◽  
Amyloid Formation ◽  
List Type ◽  
Lung Maturation ◽  
Disease Manifestation ◽  
Aβ Amyloid ◽  
Perinatal Lethality

AbstractNeurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

scholarly journals Inferring cortical function in the mouse visual system through large-scale systems neuroscience

2016 ◽  
Vol 113 (27) ◽  
pp. 7337-7344 ◽  
Author(s):  
Michael Hawrylycz ◽  
Costas Anastassiou ◽  
Anton Arkhipov ◽  
Jim Berg ◽  
Michael Buice ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Large Scale ◽  
Model Organism ◽  
Building Blocks ◽  
Mammalian Brain ◽  
Cortical Function ◽  
Scientific Mission ◽  
Large Populations ◽  
Cell Type Specific ◽  
And Behavior

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

Modeling Sleep and Wakefulness in the Thalamocortical System

2005 ◽  
Vol 93 (3) ◽  
pp. 1671-1698 ◽  
Author(s):  
Sean Hill ◽  
Giulio Tononi
Keyword(s):  
Cortical Neurons ◽  
Large Scale ◽  
Slow Waves ◽  
Slow Oscillation ◽  
Sleep Mode ◽  
Thalamic Nuclei ◽  
Slow Oscillations ◽  
Corticocortical Connections

When the brain goes from wakefulness to sleep, cortical neurons begin to undergo slow oscillations in their membrane potential that are synchronized by thalamocortical circuits and reflected in EEG slow waves. To provide a self-consistent account of the transition from wakefulness to sleep and of the generation of sleep slow waves, we have constructed a large-scale computer model that encompasses portions of two visual areas and associated thalamic and reticular thalamic nuclei. Thousands of model neurons, incorporating several intrinsic currents, are interconnected with millions of thalamocortical, corticothalamic, and both intra- and interareal corticocortical connections. In the waking mode, the model exhibits irregular spontaneous firing and selective responses to visual stimuli. In the sleep mode, neuromodulatory changes lead to slow oscillations that closely resemble those observed in vivo and in vitro. A systematic exploration of the effects of intrinsic currents and network parameters on the initiation, maintenance, and termination of slow oscillations shows the following. 1) An increase in potassium leak conductances is sufficient to trigger the transition from wakefulness to sleep. 2) The activation of persistent sodium currents is sufficient to initiate the up-state of the slow oscillation. 3) A combination of intrinsic and synaptic currents is sufficient to maintain the up-state. 4) Depolarization-activated potassium currents and synaptic depression terminate the up-state. 5) Corticocortical connections synchronize the slow oscillation. The model is the first to integrate intrinsic neuronal properties with detailed thalamocortical anatomy and reproduce neural activity patterns in both wakefulness and sleep, thereby providing a powerful tool to investigate the role of sleep in information transmission and plasticity.

scholarly journals RNA-binding protein FXR1 is presented in rat brain in amyloid form

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Julia V. Sopova ◽  
Elena I. Koshel ◽  
Tatiana A. Belashova ◽  
Sergey P. Zadorsky ◽  
Alexandra V. Sergeeva ◽  
...  
Keyword(s):  
Rat Brain ◽  
Congo Red ◽  
Cortical Neurons ◽  
Rna Binding ◽  
Rnase A ◽  
Rna Molecules ◽  
Proteomic Approach ◽  
Amyloid Oligomers ◽  
Protein Fibrils ◽  
The Brain

AbstractAmyloids are β-sheets-rich protein fibrils that cause neurodegenerative and other incurable human diseases affecting millions of people worldwide. However, a number of proteins is functional in the amyloid state in various organisms from bacteria to humans. Using an original proteomic approach, we identified a set of proteins forming amyloid-like aggregates in the brain of young healthy rats. One of them is the FXR1 protein, which is known to regulate memory and emotions. We showed that FXR1 clearly colocalizes in cortical neurons with amyloid-specific dyes Congo-Red, Thioflavines S and T. FXR1 extracted from brain by immunoprecipitation shows yellow-green birefringence after staining with Congo red. This protein forms in brain detergent-resistant amyloid oligomers and insoluble aggregates. RNA molecules that are colocalized with FXR1 in cortical neurons are insensitive to treatment with RNase A. All these data suggest that FXR1 functions in rat brain in amyloid form. The N-terminal amyloid-forming fragment of FXR1 is highly conserved across mammals. We assume that the FXR1 protein may be presented in amyloid form in brain of different species of mammals, including humans.

scholarly journals V-NeuroStack: 3D Time Stacks for Identifying Patterns in Calcium Imaging Data

2020 ◽  
Author(s):  
Ashwini G. Naik ◽  
Robert V. Kenyon ◽  
Aynaz Taheri ◽  
Tanya Berger-Wolf ◽  
Baher Ibrahim ◽  
...  
Keyword(s):  
Calcium Imaging ◽  
Cortical Neurons ◽  
Large Scale ◽  
Line Graph ◽  
Imaging Data ◽  
Web Interface ◽  
Activity Data ◽  
Spatio Temporal

AbstractBackgroundUnderstanding functional correlations between the activities of neuron populations is vital for the analysis of neuronal networks. Analyzing large-scale neuroimaging data obtained from hundreds of neurons simultaneously poses significant visualization challenges. We developed V-NeuroStack, a novel network visualization tool to visualize data obtained using calcium imaging of spontaneous activity of cortical neurons in a mouse brain slice.New MethodV-NeuroStack creates 3D time stacks by stacking 2D time frames for a period of 600 seconds. It provides a web interface that enables exploration and analysis of data using a combination of 3D and 2D visualization techniques.Comparison with existing MethodsPrevious attempts to analyze such data have been limited by the tools available to visualize large numbers of correlated activity traces. V-NeuroStack can scale data sets with at least a few thousand temporal snapshots.ResultsV-NeuroStack’s 3D view is used to explore patterns in the dynamic large-scale correlations between neurons over time. The 2D view is used to examine any timestep of interest in greater detail. Furthermore, a dual-line graph provides the ability to explore the raw and first-derivative values of a single neuron or a functional cluster of neurons.ConclusionsV-NeuroStack enables easy exploration and analysis of large spatio-temporal datasets using two visualization paradigms: (a) Space-Time cube (b)Two-dimensional networks, via web interface. It will support future advancements in in vitro and in vivo data capturing techniques and can bring forth novel hypotheses by permitting unambiguous visualization of large-scale patterns in the neuronal activity data.

scholarly journals β-Barrels and Amyloids: Structural Transitions, Biological Functions, and Pathogenesis

2021 ◽  
Vol 22 (21) ◽  
pp. 11316
Author(s):  
Anna I. Sulatskaya ◽  
Anastasiia O. Kosolapova ◽  
Alexander G. Bobylev ◽  
Mikhail V. Belousov ◽  
Kirill S. Antonets ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Biological Functions ◽  
Interspecies Interactions ◽  
Structural Relationships ◽  
Fibrillar Morphology ◽  
Dimeric Form ◽  
Functional Amyloids ◽  
Partially Unfolded

Insoluble protein aggregates with fibrillar morphology called amyloids and β-barrel proteins both share a β-sheet-rich structure. Correctly folded β-barrel proteins can not only function in monomeric (dimeric) form, but also tend to interact with one another—followed, in several cases, by formation of higher order oligomers or even aggregates. In recent years, findings proving that β-barrel proteins can adopt cross-β amyloid folds have emerged. Different β-barrel proteins were shown to form amyloid fibrils in vitro. The formation of functional amyloids in vivo by β-barrel proteins for which the amyloid state is native was also discovered. In particular, several prokaryotic and eukaryotic proteins with β-barrel domains were demonstrated to form amyloids in vivo, where they participate in interspecies interactions and nutrient storage, respectively. According to recent observations, despite the variety of primary structures of amyloid-forming proteins, most of them can adopt a conformational state with the β-barrel topology. This state can be intermediate on the pathway of fibrillogenesis (“on-pathway state”), or can be formed as a result of an alternative assembly of partially unfolded monomers (“off-pathway state”). The β-barrel oligomers formed by amyloid proteins possess toxicity, and are likely to be involved in the development of amyloidoses, thus representing promising targets for potential therapy of these incurable diseases. Considering rapidly growing discoveries of the amyloid-forming β-barrels, we may suggest that their real number and diversity of functions are significantly higher than identified to date, and represent only “the tip of the iceberg”. Here, we summarize the data on the amyloid-forming β-barrel proteins, their physicochemical properties, and their biological functions, and discuss probable means and consequences of the amyloidogenesis of these proteins, along with structural relationships between these two widespread types of β-folds.

Purification of the Antihemophilic Factor by Gel Filtration on Agarose

1969 ◽  
Vol 22 (03) ◽  
pp. 577-583 ◽  
Author(s):  
M.M.P Paulssen ◽  
A.C.M.G.B Wouterlood ◽  
H.L.M.A Scheffers
Keyword(s):  
Factor Viii ◽  
Plasma Proteins ◽  
Large Scale ◽  
Gel Filtration ◽  
Large Scale Preparation ◽  
Scale Preparation ◽  
Antihemophilic Factor

SummaryFactor VIII can be isolated from plasma proteins, including fibrinogen by chromatography on agarose. The best results were obtained with Sepharose 6B. Large scale preparation is also possible when cryoprecipitate is separated by chromatography. In most fractions containing factor VIII a turbidity is observed which may be due to the presence of chylomicrons.The purified factor VIII was active in vivo as well as in vitro.

Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

2020 ◽  
Vol 26 ◽  
Author(s):  
Luíza Dantas-Pereira ◽  
Edézio F. Cunha-Junior ◽  
Valter V. Andrade-Neto ◽  
John F. Bower ◽  
Guilherme A. M. Jardim ◽  
...  
Keyword(s):  
Large Scale ◽  
Neglected Tropical Diseases ◽  
Folk Medicine ◽  
Leishmania Species ◽  
Parasitic Infections ◽  
Mechanistic Analysis ◽  
Leishmania Spp ◽  
Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 141-157 ◽  
Author(s):  
Dubravka S. Strac ◽  
Marcela Konjevod ◽  
Matea N. Perkovic ◽  
Lucija Tudor ◽  
Gordana N. Erjavec ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Comprehensive Overview ◽  
Brain Functions ◽  
Specific Effects ◽  
And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

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