Neuronal innervation regulates the secretion of neurotrophic myokines and exosomes from skeletal muscle

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(19)

Опубликована: Апрель 29, 2024

Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported promote muscle secretion, little is known about the effects of neuronal innervation activity on yield molecular composition biologically active molecules muscle. As neuromuscular diseases disabilities associated with denervation impact metabolism, we hypothesize that firing may pivotal regulating secretion activities muscles. We examined this hypothesis using an engineered tissue model consisting muscles innervated by motor neurons. The displayed elevated expression mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived factor, FDNC5, well mRNA peroxisome-proliferator-activated receptor γ coactivator 1α, key regulator metabolism. Upon glutamate stimulation, secreted higher levels irisin exosomes containing more diverse microRNAs than neuron-free Consequently, biological factors enhanced branching, axonal transport, and, ultimately, spontaneous network primary hippocampal neurons vitro. Overall, these results reveal importance modulating muscle-derived function suggest holds promise platform for producing molecules.

Язык: Английский

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Blood biomarkers and treatment response in major depression

Expert Review of Molecular Diagnostics, Год журнала: 2018, Номер 18(6), С. 513 - 529

Опубликована: Апрель 27, 2018

Introduction: Millions of people worldwide suffer from depression, but despite advances in pharmacological therapies, many patients do not experience symptomatic remission or treatment response, even after treatments with several medications. As such, there is an urgent need to identify biomarkers that can only predict the response also allow a rational selection optimal therapy for each patient.Areas covered: This review examines recent findings, coming different 'omic sciences,' human blood-based associated antidepressant particular attention on genetic/epigenetic and biochemical biomarkers. Specific emphasis will be placed key molecules related neuroplasticity inflammation because their involvement pathophysiology depression response.Expert commentary: Biomarker identification still ongoing work. Indeed, date, no have sufficiently proven specificity, sensitivity, reproducibility used clinical setting. However, 'omic' approaches hold great promise identifying multiple features predicting making personalized strategy possible patient, thereby assist quick efficacious responsiveness. It thus necessary future studies take integrative approach includes assessment, environment influences, molecular biological

Язык: Английский

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Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics

Neuropsychopharmacology, Год журнала: 2019, Номер 45(4), С. 656 - 665

Опубликована: Ноя. 27, 2019

Abstract The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them a novel effective method cell-to-cell communication. However, little is about the role exosome-secreted miRNAs in regulation glutamate receptor gene expression relevance for schizophrenia (SCZ) bipolar disorder (BD). Using mature miRNA profiling quantitative real-time PCR (qRT-PCR) orbitofrontal cortex (OFC) SCZ ( N = 29; 20 male 9 female), BD 26; 12 14 unaffected control 25; 21 4 female) subjects, we uncovered that miR-223, an targets receptors, was increased at level OFC patients with positive history psychosis time death inversely associated deficits its ionotropic NMDA-type subunit 2B GRIN2B ) AMPA-type 2 GRIA2 ). Furthermore, changes miR-223 levels were positively negatively correlated inflammatory GABAergic expression, respectively. Moreover, found be enriched astrocytes secreted exosomes, antipsychotics shown cellular exosomal localization cell-specific manner. addition astrocytic cultures resulted significant increase notable reduction Grin2b Gria2 mRNA levels, which strongly expression. Lastly, inhibition abrogated exosomal-mediated Taken together, our results demonstrate secretion psychosis-altered glial-enriched controls regulated by antipsychotics.

Язык: Английский

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miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

Cells, Год журнала: 2020, Номер 9(1), С. 220 - 220

Опубликована: Янв. 15, 2020

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing degradation of target mRNA or translational repression. MiRNAs involved in control a multiplicity biological processes, and their absence altered has been associated with variety human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have described as mediators intercellular communication multiple contexts, tumor microenvironment. Cancer cells cooperate stromal elements matrix (ECM) to establish comfortable niche grow, evade immune system, expand. Within microenvironment, release ECmiRNAs other factors order influence hijack physiological processes surrounding cells, fostering progression. Here, we discuss role pathogenesis multicomplex such Alzheimer’s disease, obesity, cancer, focusing on contribution both intracellular miRNAs, released establishment development cancer niche. We also review growing evidence suggesting use novel targets potential tools for therapeutic applications.

Язык: Английский

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Dysregulation of miRNA and its potential therapeutic application in schizophrenia

CNS Neuroscience & Therapeutics, Год журнала: 2018, Номер 24(7), С. 586 - 597

Опубликована: Март 12, 2018

Summary Although it is generally believed that genetic and developmental factors play critical roles in pathogenesis of schizophrenia, however, the precise etiological mechanism schizophrenia remains largely unknown. Over past decades, mi RNA s have emerged as an essential post‐transcriptional regulator gene expression regulation. The importance brain development neuroplasticity has been well‐established. Abnormal dysfunction are known to involve pathophysiology many neuropsychiatric diseases including schizophrenia. In this review, we summarized recent findings schizophrenia‐associated dysregulation functional We also discussed potential therapeutic implications regulation illness.

Язык: Английский

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Emerging Roles for 3′ UTRs in Neurons

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(10), С. 3413 - 3413

Опубликована: Май 12, 2020

The 3' untranslated regions (3' UTRs) of mRNAs serve as hubs for post-transcriptional control the targets microRNAs (miRNAs) and RNA-binding proteins (RBPs). Sequences in UTRs confer alterations mRNA stability, direct localization to subcellular regions, impart translational control. Thousands are localized compartments neurons-including axons, dendrites, synapses-where they thought undergo local translation. Despite an established role UTR sequences imparting neurons, specific RNA structural features at play remain poorly understood. nervous system selectively expresses longer isoforms via alternative polyadenylation (APA). regulation APA neurons neuronal functions starting be uncovered. Surprising roles emerging beyond protein synthesis include RBP delivery scaffolds regulators splicing. Evidence is also that can cleaved, leading stable, isolated fragments which unknown function. Mutations implicated several neurological disorders-more studies needed uncover how these mutations impact gene what their relationship disease severity.

Язык: Английский

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Germline AGO2 mutations impair RNA interference and human neurological development

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Ноя. 16, 2020

Abstract ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational degradation as part of RNA interference pathway. Despite essential nature this process cellular function, there is little information on role RISC components in human development organ function. We identify 13 heterozygous mutations AGO2 21 patients affected by disturbances neurological development. Each identified single amino acid result impaired shRNA-mediated silencing. observe either formation or increased binding to mRNA mutation specific functional consequences. The latter supported decreased phosphorylation a C-terminal serine cluster involved target release, dendritic P-bodies neurons global transcriptome alterations patient-derived primary fibroblasts. Our data emphasize importance gene expression regulation through dynamic AGO2-RNA association neuronal

Язык: Английский

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The role of synaptic microRNAs in Alzheimer's disease

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2020, Номер 1866(12), С. 165937 - 165937

Опубликована: Авг. 20, 2020

Язык: Английский

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MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

Proceedings of the National Academy of Sciences, Год журнала: 2019, Номер 116(12), С. 5727 - 5736

Опубликована: Фев. 26, 2019

Homeostatic synaptic scaling is a negative feedback response to fluctuations in strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the apparatus have been characterized, intrinsic regulatory mechanisms promoting remain largely unknown. MicroRNAs may contribute posttranscriptional control mRNAs implicated different stages scaling, but their role these still undervalued. Here, we report that chronic blockade glutamate receptors AMPA and NMDA types hippocampal neurons culture induces changes mRNA miRNA transcriptomes, leading upscaling. Specifically, show persistently down-regulates miR-186-5p. Moreover, describe conserved miR-186-5p-binding site within 3′UTR encoding receptor GluA2 subunit, demonstrate direct target Overexpression miR-186 decreased surface levels, increased expression GluA2-lacking receptors, blocked whereas inhibition miR-186-5p levels amplitude frequency receptor-mediated currents, mimicked excitatory inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation expression.

Язык: Английский

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Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function

Scientific Reports, Год журнала: 2019, Номер 9(1)

Опубликована: Март 5, 2019

Abstract Injury to retinal ganglion cells (RGC), central nervous system neurons that relay visual information the brain, often leads RGC axon degeneration and permanently lost function. Herein this study shows matrix-bound nanovesicles (MBV), a distinct class of extracellular nanovesicle localized specifically matrix (ECM) healthy tissues, can neuroprotect RGCs preserve function after severe, intraocular pressure (IOP) induced ischemia in rat. Intravitreal MBV injections attenuated IOP-induced death, protected connectivity nuclei prevented loss as shown by histology, anterograde tracing, manganese-enhanced magnetic resonance imaging, electroretinography. In optic nerve, also decreases growth associated protein-43 increases glial fibrillary acidic protein. vitro studies showed suppressed pro-inflammatory signaling activated microglia astrocytes, stimulated neurite growth, neuroprotected from neurotoxic media conditioned astrocytes. Thus, positively modulate pathways (e.g., inflammation, cell growth) diverse types. Since are naturally derived, bioactive factors present numerous FDA approved devices, may be readily useful, not only experimentally, but clinically immunomodulatory, neuroprotective for treating trauma or disease retina well other CNS tissues.

Язык: Английский

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