scholarly journals Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity

2021 ◽  
Vol 22 (12) ◽  
pp. 6435
Author(s):  
Marco Diociaiuti ◽  
Roberto Bonanni ◽  
Ida Cariati ◽  
Claudio Frank ◽  
Giovanna D’Arcangelo
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Damage ◽  
Large Family ◽  
Synaptic Proteins ◽  
Common Mechanism ◽  
Membrane Composition ◽  
Neuron Membrane ◽  
Common Structure ◽  
Membrane Spanning ◽  
Induced Neuron

It has been proposed that a “common core” of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer’s, Parkinson’s, type II diabetes and Creutzfeldt–Jacob’s Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific “common structure” of the toxic aggregate, and a “common mechanism” by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission.

Growth Hormone Enhances Excitatory Synaptic Transmission in Area CA1 of Rat Hippocampus

2006 ◽  
Vol 95 (5) ◽  
pp. 2962-2974 ◽  
Author(s):  
Ghada S. Mahmoud ◽  
Lawrence M. Grover
Keyword(s):  
Growth Hormone ◽  
Synaptic Transmission ◽  
Pi3 Kinase ◽  
Janus Kinase ◽  
Excitatory Synaptic Transmission ◽  
Common Mechanism ◽  
Hippocampal Function ◽  
Short Term ◽  
Area Ca1 ◽  
Short Term Effects

The hippocampus produces growth hormone (GH) and contains GH receptors, suggesting a potential role for GH signaling in the regulation of hippocampal function. In agreement with this possibility, previous investigations have found altered hippocampal function and hippocampal-dependent learning and memory after chronic GH administration or deficiency. In this study we applied GH to in vitro rat hippocampal brain slices, to determine whether GH has short-term effects on hippocampal function in addition to previously documented chronic effects. We found that GH enhanced both AMPA- and NMDA-receptor–mediated excitatory postsynaptic potentials (EPSPs) in hippocampal area CA1, but did not alter GABAA-receptor–mediated inhibitory synaptic transmission. GH enhancement of excitatory synaptic transmission was gradual, requiring 60–70 min to reach maximum, and occurred without any change in paired-pulse facilitation, suggesting a possible postsynaptic site of action. In CA1 pyramidal neurons, GH enhancement of EPSPs was correlated with significant hyperpolarization and decreased input resistance. GH enhancement of EPSPs required Janus kinase 2 (JAK2), phosphatidylinositol-3 (PI3) kinase, mitogen-activated protein (MAP) kinase kinase (MEK), and synthesis of new proteins. Although PI3 kinase and MEK were required for initiation of GH effects on excitatory synaptic transmission, they were not required for maintained enhancement of EPSPs. GH treatment and tetanus-induced long-term potentiation were mutually occluding, suggesting a common mechanism or mechanisms in both forms of synaptic enhancement. Our results demonstrate that GH has powerful short-term effects on hippocampal function, and extend the timescale for potential roles of GH in regulating hippocampal function and hippocampal-dependent behaviors.

scholarly journals Synaptic transmission induces site-specific changes in sialylation on N-linked glycoproteins in rat nerve terminals

2020 ◽  
Author(s):  
Inga Boll ◽  
Pia Jensen ◽  
Veit Schwämmle ◽  
Martin R. Larsen
Keyword(s):  
Synaptic Transmission ◽  
Structure And Function ◽  
Synaptic Proteins ◽  
Nerve Terminals ◽  
Membrane Glycoproteins ◽  
Site Specific ◽  
Specific Alteration ◽  
And Function ◽  
Rat Nerve ◽  
Stimulation Of

AbstractSynaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show a novel potential modulator of synaptic transmission, sialylation of N-linked glycosylation. The negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after five seconds depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

A DrosophilaSNAP-25Null Mutant Reveals Context-Dependent Redundancy WithSNAP-24in Neurotransmission

Genetics ◽  
2002 ◽  
Vol 162 (1) ◽  
pp. 259-271 ◽  
Author(s):  
Ilya Vilinsky ◽  
Bryan A Stewart ◽  
James Drummond ◽  
Iain Robinson ◽  
David L Deitcher
Keyword(s):  
Synaptic Transmission ◽  
Larval Stage ◽  
Neurotransmitter Release ◽  
Synaptic Proteins ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Mutant Form ◽  
F1 Progeny ◽  
Sensitive Allele ◽  
Pharate Adult

AbstractThe synaptic protein SNAP-25 is an important component of the neurotransmitter release machinery, although its precise function is still unknown. Genetic analysis of other synaptic proteins has yielded valuable information on their role in synaptic transmission. In this study, we performed a mutagenesis screen to identify new SNAP-25 alleles that fail to complement our previously isolated recessive temperature-sensitive allele of SNAP-25, SNAP-25ts. In a screen of 100,000 flies, 26 F1 progeny failed to complement SNAP-25ts and 21 of these were found to be null alleles of SNAP-25. These null alleles die at the pharate adult stage and electroretinogram recordings of these animals reveal that synaptic transmission is blocked. At the third instar larval stage, SNAP-25 nulls exhibit nearly normal neurotransmitter release at the neuromuscular junction. This is surprising since SNAP-25ts larvae exhibit a much stronger synaptic phenotype. Our evidence indicates that a related protein, SNAP-24, can substitute for SNAP-25 at the larval stage in SNAP-25 nulls. However, if a wild-type or mutant form of SNAP-25 is present, then SNAP-24 does not appear to take part in neurotransmitter release at the larval NMJ. These results suggest that the apparent redundancy between SNAP-25 and SNAP-24 is due to inappropriate genetic substitution.

scholarly journals Effects of long-lasting social isolation and re-socialization on cognitive performance and brain activity: a longitudinal study in Octodon degus

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniela S. Rivera ◽  
Carolina B. Lindsay ◽  
Carolina A. Oliva ◽  
Juan Francisco Codocedo ◽  
Francisco Bozinovic ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Social Isolation ◽  
Stress Responses ◽  
Brain Activity ◽  
Synaptic Proteins ◽  
Stressful Situation ◽  
Social Emotional ◽  
Octodon Degus ◽  
Socially Isolated

Abstract Social isolation is considered a stressful situation that results in increased physiological reactivity to novel stimuli, altered behaviour, and impaired brain function. Here, we investigated the effects of long-term social isolation on working memory, spatial learning/memory, hippocampal synaptic transmission, and synaptic proteins in the brain of adult female and male Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects, makes it a unique animal model that can be highly applicable for further social, emotional, cognitive, and aging studies. These animals were socially isolated from post-natal and post-weaning until adulthood. We also evaluated if re-socialization would be able to compensate for reactive stress responses in chronically stressed animals. We showed that long-term social isolation impaired the HPA axis negative feedback loop, which can be related to cognitive deficits observed in chronically stressed animals. Notably, re-socialization restored it. In addition, we measured physiological aspects of synaptic transmission, where chronically stressed males showed more efficient transmission but deficient plasticity, as the reverse was true on females. Finally, we analysed synaptic and canonical Wnt signalling proteins in the hypothalamus, hippocampus, and prefrontal cortex, finding both sex- and brain structure-dependent modulation, including transient and permanent changes dependent on stress treatment.

scholarly journals Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 961 ◽  
Author(s):  
Darryll Oliver ◽  
P. Reddy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Cell Cultures ◽  
Neuronal Damage ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Large Family ◽  
Related Protein

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.

scholarly journals A volumetric framework for quantum computer benchmarks

Quantum ◽  
2020 ◽  
Vol 4 ◽  
pp. 362
Author(s):  
Robin Blume-Kohout ◽  
Kevin C. Young
Keyword(s):  
Quantum Computer ◽  
Pareto Frontier ◽  
Large Family ◽  
Test Suite ◽  
Large Set ◽  
Common Structure ◽  
Time Space ◽  
Trade Offs ◽  
Graphical Summary ◽  
Quantum Volume

We propose a very large family of benchmarks for probing the performance of quantum computers. We call them volumetric benchmarks (VBs) because they generalize IBM's benchmark for measuring quantum volume \cite{Cross18}. The quantum volume benchmark defines a family of square circuits whose depth d and width w are the same. A volumetric benchmark defines a family of rectangular quantum circuits, for which d and w are uncoupled to allow the study of time/space performance trade-offs. Each VB defines a mapping from circuit shapes — (w,d) pairs — to test suites C(w,d). A test suite is an ensemble of test circuits that share a common structure. The test suite C for a given circuit shape may be a single circuit C, a specific list of circuits {C1…CN} that must all be run, or a large set of possible circuits equipped with a distribution Pr(C). The circuits in a given VB share a structure, which is limited only by designers' creativity. We list some known benchmarks, and other circuit families, that fit into the VB framework: several families of random circuits, periodic circuits, and algorithm-inspired circuits. The last ingredient defining a benchmark is a success criterion that defines when a processor is judged to have ``passed'' a given test circuit. We discuss several options. Benchmark data can be analyzed in many ways to extract many properties, but we propose a simple, universal graphical summary of results that illustrates the Pareto frontier of the d vs w trade-off for the processor being benchmarked.

scholarly journals Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

2021 ◽  
Author(s):  
Julie Bourseguin ◽  
Wen Cheng ◽  
Emily Talbot ◽  
Liana Hardy ◽  
Svetlana V. Khoronenkova
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Genome Instability ◽  
Neuronal Damage ◽  
Common Mechanism ◽  
Atm Kinase ◽  
Human Microglia ◽  
Neuronal Processes ◽  
The Central Nervous System ◽  
Underlying Mechanisms

The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimer′s and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia telangiectasia, potentially contributing to neurodegeneration.

scholarly journals Catalpol protects synaptic proteins from beta-amyloid induced neuron injury and improves cognitive functions in aged rats

Oncotarget ◽  
2017 ◽  
Vol 8 (41) ◽  
pp. 69303-69315 ◽  
Author(s):  
Zhiming Xia ◽  
Fengfei Wang ◽  
Shuang Zhou ◽  
Rui Zhang ◽  
Fushun Wang ◽  
...  
Keyword(s):  
Cognitive Functions ◽  
Beta Amyloid ◽  
Synaptic Proteins ◽  
Aged Rats ◽  
Induced Neuron ◽  
Neuron Injury

scholarly journals Depolarization-dependent Induction of Site-specific Changes in Sialylation on N-linked Glycoproteins in Rat Nerve Terminals

2020 ◽  
Vol 19 (9) ◽  
pp. 1418-1435
Author(s):  
Inga Boll ◽  
Pia Jensen ◽  
Veit Schwämmle ◽  
Martin R. Larsen
Keyword(s):  
Synaptic Transmission ◽  
Neurotransmitter Release ◽  
Synaptic Proteins ◽  
Nerve Terminals ◽  
Membrane Glycoproteins ◽  
Site Specific ◽  
Specific Alteration ◽  
And Function ◽  
Rat Nerve ◽  
Stimulation Of

Synaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show that sialylation of N-linked glycosylation is a novel potential modulator of neurotransmitter release mechanisms by investigating depolarization-dependent changes of formerly sialylated N-linked glycopeptides. We suggest that negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after 5 s depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

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