Kallistatin leads to cognition impairment via downregulating glutamine synthetase

Pharmacological Research, Journal Year: 2024, Volume and Issue: 202, P. 107145 - 107145

Published: March 14, 2024

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role glutamate-glutamine cycle homeostasis remains unclear. this study, we identified impaired function transgenic (KAL-TG) mice. Baseline glutamate levels were elevated miniature excitatory postsynaptic current (mEPSC) frequency was increased hippocampus, suggesting impairment KAL-TG Mechanistically, demonstrated that promoted lysine acetylation ubiquitination glutamine synthetase (GS) facilitated its degradation via proteasome pathway, thereby downregulating GS. Fenofibrate improved memory mice by serum Kallistatin. Collectively, our study findings provide insights mechanism which regulates impairment, suggest potential fenofibrate to prevente treat AD high

Language: Английский

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Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics

Cells, Journal Year: 2020, Volume and Issue: 9(4), P. 835 - 835

Published: March 31, 2020

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) GTPase-activating (GAPs). transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such growth, migration, adhesion, differentiation. In particular, play essential roles in neuronal morphology function. Recent evidence suggests dysfunction GTPase signaling contributes substantially pathogenesis autism spectrum disorder (ASD). It has been found 20 genes encoding regulators effectors listed ASD risk Simons foundation research initiative (SFARI). This review summarizes clinical evidence, protein structure, expression pattern these genes. Moreover, ASD-related behavioral phenotypes animal models reviewed, therapeutic approaches show successful treatment effects discussed.

Language: Английский

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The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

Frontiers in Synaptic Neuroscience, Journal Year: 2020, Volume and Issue: 12

Published: April 17, 2020

The ability to form memories in the brain is an important process needed for daily functions and its impairment associated with human mental disorders. Evidence indicates that long-term memory (LTM) related processes such as consolidation, extinction forgetting involve changes of synaptic efficacy produced by alterations neural transmission morphology. Modulation number dendritic spines their morphology has been proposed contribute neuronal mediating LTM processes. Rac GTPase activity regulated activation it can affect spine controlling actin-regulatory proteins. Recent evidence shows extinction, erasure areas mediate these behaviors. Altered abnormal By affecting we further understand roles morphogenesis memory. Moreover, manipulation may serve a therapeutic tool treatment memory-related diseases.

Language: Английский

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Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Oct. 4, 2021

Memory impairments are associated with many brain disorders such as autism, Alzheimer's disease, and depression. Forming memories involves modifications of synaptic transmission spine morphology. The Rho family small GTPases key regulators plasticity by affecting various downstream molecules to remodel the actin cytoskeleton. In this paper, we will review recent studies on roles proteins in regulation hippocampal long-term potentiation (LTP) depression (LTD), most extensively studied forms widely regarded cellular mechanisms for learning memory. We also discuss involvement signaling morphology, structural basis memory formation. Finally, association between abnormalities function. It is expected that studying at synapse contribute understanding how formed disrupted diseases.

Language: Английский

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Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Nov. 24, 2022

Inhibition of Glycogen synthase kinase 3 (GSK3) is a popular explanation for the effects lithium ions on mood regulation in bipolar disorder and other mental illnesses, including major depression, cyclothymia, schizophrenia. Contribution GSK3 supported by evidence obtained from animal patient derived model systems. However, two enzymes, GSK3α GSK3β, have more than 100 validated substrates. They are thus central hubs biological functions, such as dopamine-glutamate neurotransmission, synaptic plasticity (Hebbian homeostatic), inflammation, circadian regulation, protein synthesis, metabolism, mitochondrial functions. The intricate contributions to several processes make it difficult identify specific mechanisms stabilization therapeutic development. Identification substrates involved action critical. We provide an overview functions which there contribution effects. A particular focus given four these: transcription factor cAMP response element-binding (CREB), RNA-binding FXR1, kinesin subunits, cytoskeletal regulator CRMP2. An how co-regulation these may result shared outcomes also presented. Better understanding inhibition contributes should allow identification targets future drug It framework overlap with those drugs ketamine antipsychotics, inhibit brain GSK3.

Language: Английский

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Torasemide Improves the Propionic Acid-Induced Autism in Rats: A Histopathological and Imaging Study

ALPHA PSYCHIATRY, Journal Year: 2023, Volume and Issue: 24(1), P. 22 - 31

Published: Jan. 10, 2023

Autism spectrum disorder is a neurodevelopmental disease in which impaired social behaviors, sociality, and restricted repetitive behaviors are seen. Bumetanide loop diuretic that inhibits Na+-K+-2Cl- cotransporter 1 it currently used clinical phase studies patients with autism disorder. In present research, purposed to demonstrate the beneficial effects of torasemide another inhibitor on an experimental model induced propionic acid by providing imaging brain tissue investigations. Male Wistar rats were study (n = 30). Propionic 250 mg/kg/day was administrated intraperitoneally induce for 5 days. Three groups created as follows: group 1, normal control 10); 2, saline given 3, + tora-semide-administrated 10). Torasemide scored higher behavioral tests compared group. The levels malondialdehyde, tumor necrosis factor-alpha, interleukin-2, interleukin-17, Nuclear Factor kappa B (NF-κB), Glial fibrillary acidic protein (GFAP) remarkably histopathology assessments, had neuronal count Cornu Ammonis 2 hippocampus, Purkinje cells cerebellum. GFAP immunostaining index (Cornu 1) cerebellum lower Magnetic resonance spectroscopy revealed mean lactate value Our results showed might enhance gamma-aminobutyric activity. can be considered promising treatment longer half-life less side after further studies.

Language: Английский

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Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non‐Genetic Neuromodulation

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(8)

Published: Oct. 9, 2023

Abstract Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment neurological diseases. However, developing non‐invasive well‐controllable system to deliver accurate effective stimulation challenging. Micro/nanorobots have shown great potential in various biomedical applications because their precise controllability. Here, magnetically‐manipulated optoelectronic hybrid microrobot (MOHR) presented optically targeted non‐genetic neuromodulation. By integrating magnetic component into metal–insulator–semiconductor junction design, MOHR has excellent controllability properties. The displays variety manipulation modes that enables efficient navigation different biofluids. Furthermore, could achieve precision at single‐cell level its targeting ability. This achieved by MOHR's photoelectric response visible light irradiation, which enhances excitability cells. Finally, it MOHRs effectively restore neuronal activity neurons damaged β‐amyloid, pathogenic agent Alzheimer's disease. coupling with properties, strategy on‐demand optical

Language: Английский

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Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 13

Published: Jan. 14, 2020

Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both have strong genetic basis, share similar social communication deficits co-occurring impairments of reading or language. However, whether these two common risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) the small GTPase Rac1, is one few genes that associated ASD dyslexia. Dock4 important neuronal development behaviors. Two variations, Exon27-52 deletion (protein product: Dock4-945VS) missense mutation at rs2074130 Dock4-R853H), and/or difficulties. The present study explores molecular cellular functions variants on development, by comparing them wild-type protein. Notably, it revealed mutants showed decreased ability to activate not only but also another Rap1. Consistently, were dysfunctional regulation cell morphology cytoskeleton. Using Neuro-2a cells hippocampus neurons as models, we found had compromised function promoting neurite outgrowth dendritic spine formation. Electrophysiological recordings further R853H partially lost promote excitatory synaptic transmission, whereas 945VS totally ability. Together, identified R853 previously uncharacterized site integrity function, provides insights understanding pathophysiology

Language: Английский

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Autism Spectrum Disorder/Intellectual Disability-Associated Mutations in Trio Disrupt Neuroligin 1-Mediated Synaptogenesis

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(37), P. 7768 - 7778

Published: Aug. 5, 2021

We recently identified an autism spectrum disorder/intellectual disability (ASD/ID)-related de novo mutation hotspot in the Rac1-activating GEF1 domain of protein Trio. Trio is a Rho guanine nucleotide exchange factor (RhoGEF) that essential for glutamatergic synapse function. An ASD/ID-related Trio9s domain, D1368V, produces pathologic increase synaptogenesis, suggesting coupled to synaptic regulatory mechanisms govern formation. However, molecular by which regulates synapses are largely unexplored. Here, using biochemical methods, we identify interaction between and synaptogenic Neuroligin 1 (NLGN1) brain. Molecular biological approaches were then combined with super-resolution dendritic spine imaging whole-cell voltage-clamp electrophysiology hippocampal slices from male female rats examine impact mutations have on NLGN1-mediated synaptogenesis. find eighth spectrin repeat region, N1080I, inhibits NLGN1 prevents D1368V-mediated Inhibiting via N1080I blocked synaptogenesis increases NMDA Receptor function but not AMPA Finally, show aberrant produced D1368V dependent NLGN signaling. Our findings demonstrate able pathologically as well decrease NLGN-mediated effects neurotransmission, point NLGN1-Trio part key pathway involved ASD/ID etiology. SIGNIFICANCE STATEMENT A number genes been implicated development (ASD/ID) humans. It now important relationships these uncover specific cellular pathways contribute disorders. In this study, discover two proteins ASD/ID, 1, interact one another promote also either inhibit or augment 1-mediated Together, our results that, when disrupted, likely contributes ASD/ID. Going forward, it will be determine whether represents convergence other

Language: Английский

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Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism

Neuropsychopharmacology, Journal Year: 2021, Volume and Issue: 47(6), P. 1271 - 1279

Published: Oct. 26, 2021

Language: Английский

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