Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dysregulation of miRNA and its potential therapeutic application in schizophrenia.

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

SUBMITTER: Cao T

PROVIDER: S-EPMC6490029 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Dysregulation of miRNA and its potential therapeutic application in schizophrenia.

Cao Ting T Zhen Xue-Chu XC

CNS neuroscience & therapeutics 20180312 7

Although it is generally believed that genetic and developmental factors play critical roles in pathogenesis of schizophrenia, however, the precise etiological mechanism of schizophrenia remains largely unknown. Over past decades, miRNAs have emerged as an essential post-transcriptional regulator in gene expression regulation. The importance of miRNA in brain development and neuroplasticity has been well-established. Abnormal expression and dysfunction of miRNAs are known to involve in the patho ...[more]

PMID: 29529357

Similar Datasets

Implications of SNP-triggered miRNA dysregulation in Schizophrenia development.

Project description:This review examines the substantial involvement of Single Nucleotide Polymorphisms (SNPs) and microRNAs (miRNAs) in the etiology and susceptibility to Schizophrenia, with particular emphasis on the dopaminergic, glutamatergic, and GABAergic systems. It elucidates the potential of SNPs to disrupt miRNA-mRNA interactions, leading to alterations in the regulatory mechanisms of Schizophrenia risk genes and subsequently influencing the susceptibility to Schizophrenia. Specific attention is given to the impact of SNPs in DICER, DROSHA, and DGCR8, as well as the potential for changes in DRD2 gene expression driven by miR-9 and miR-326, heightening the likelihood of Schizophrenia development. Furthermore, the review explores genetic alterations in the glutamatergic system, focusing on modifications linked to GRIN2A and its associated miRNAs, which have been reported to have a notable impact on the occurrence of Schizophrenia. Knowledge of the involvement of SNPs within miRNAs in influencing the expression of essential genes within the GABA system are emerging and described in this review, including their potential consequences for Schizophrenia.

| S-EPMC10853439 | biostudies-literature

Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion.

Project description:22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A(+/-) mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion, and we demonstrate that this reduction alters dendritic and spine development. miR-185 represses, through an evolutionarily conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus and shows higher prenatal brain expression. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A(+/-) mice and results in structural alterations in the hippocampus. Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction.

| S-EPMC3556818 | biostudies-literature

Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.

Project description:Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

| S-EPMC4856588 | biostudies-literature

Potential Roles of Redox Dysregulation in the Development of Schizophrenia.

Project description:Converging evidence implicates redox dysregulation as a pathological mechanism driving the emergence of psychosis. Increased oxidative damage and decreased capacity of intracellular redox modulatory systems are consistent findings in persons with schizophrenia as well as in persons at clinical high risk who subsequently developed frank psychosis. Levels of glutathione, a key regulator of cellular redox status, are reduced in the medial prefrontal cortex, striatum, and thalamus in schizophrenia. In humans with schizophrenia and in rodent models recapitulating various features of schizophrenia, redox dysregulation is linked to reductions of parvalbumin containing gamma-aminobutyric acid (GABA) interneurons and volumes of their perineuronal nets, white matter abnormalities, and microglia activation. Importantly, the activity of transcription factors, kinases, and phosphatases regulating diverse aspects of neurodevelopment and synaptic plasticity varies according to cellular redox state. Molecules regulating interneuron function under redox control include NMDA receptor subunits GluN1 and GluN2A as well as KEAP1 (regulator of transcription factor NRF2). In a rodent schizophrenia model characterized by impaired glutathione synthesis, the Gclm knockout mouse, oxidative stress activated MMP9 (matrix metalloprotease 9) via its redox-responsive regulatory sites, causing a cascade of molecular events leading to microglia activation, perineural net degradation, and impaired NMDA receptor function. Molecular pathways under redox control are implicated in the etiopathology of schizophrenia and are attractive drug targets for individualized drug therapy trials in the contexts of prevention and treatment of psychosis.

| S-EPMC7395886 | biostudies-literature

Temporal dynamics of miRNAs in human DLPFC and its association with miRNA dysregulation in schizophrenia.

Project description:Brain development is dependent on programmed gene expression, which is both genetically and epigenetically regulated. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is essential for brain development. As abnormal brain development is hypothesized to be associated with schizophrenia, miRNAs are an intriguing target for this disorder. The aims of this study were to determine the temporal dynamics of miRNA expression in the human dorsolateral prefrontal cortex (DLPFC), and the relationship between miRNA's temporal expression pattern and dysregulation in schizophrenia. This study used next-generation sequencing to characterize the temporal dynamics of miRNA expression in the DLPFC of 109 normal subjects (second trimester-74 years of age) and miRNA expression changes in 34 schizophrenia patients. Unlike mRNAs, the majority of which exhibits a wave of change in fetuses, most miRNAs are preferentially expressed during a certain period before puberty. It is noted that in schizophrenia patients, miRNAs normally enriched in infants tend to be upregulated, while those normally enriched in prepuberty tend to be downregulated, and the targets of these miRNAs are enriched for genes encoding synaptic proteins and those associated with schizophrenia. In addition, miR-936 and miR-3162 were found to be increased in the DLPFC of patients with schizophrenia. These findings reveal the temporal dynamics of miRNAs in the human DLPFC, implicate the importance of miRNAs in DLPFC development, and suggest a possible link between schizophrenia and dysregulation of miRNAs enriched in infancy and prepuberty.

| S-EPMC6702224 | biostudies-literature

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

Project description:A convergence of evidence shows that use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at which psychotic symptoms first manifest. Cannabis exposure during adolescence is most strongly associated with the onset of psychosis amongst those who are particularly vulnerable, such as those who have been exposed to child abuse and those with family histories of schizophrenia. Schizophrenia that develops after cannabis use may have a unique clinical phenotype, and several genetic polymorphisms may modulate the relationship between cannabis use and psychosis. The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia. Anandamide signaling in the central nervous system may be particularly important. Δ(9)-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects. CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties. Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research.

| S-EPMC4604190 | biostudies-literature

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.

Project description:MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.

| S-EPMC8601628 | biostudies-literature

Variability in Cardiac miRNA-122 Level Determines Therapeutic Potential of miRNA-Regulated AAV Vectors.

Project description:Systemically delivered adeno-associated viral vector serotype 9 (AAV9) effectively transduces murine heart, but provides transgene expression also in liver and skeletal muscles. Improvement of the selectivity of transgene expression can be achieved through incorporation of target sites (TSs) for miRNA-122 and miRNA-206 into the 3' untranslated region (3' UTR) of the expression cassette. Here, we aimed to generate such miRNA-122- and miRNA-206-regulated AAV9 vector for a therapeutic, heart-specific overexpression of heme oxygenase-1 (HO-1). We successfully validated the vector functionality in murine cell lines corresponding to tissues targeted by AAV9. Next, we evaluated biodistribution of transgene expression following systemic vector delivery to HO-1-deficient mice of mixed C57BL/6J × FVB genetic background. Although AAV genomes were present in the hearts of these animals, HO-1 protein expression was either absent or significantly impaired. We found that miRNA-122, earlier described as liver specific, was present also in the hearts of C57BL/6J × FVB mice. Various levels of miRNA-122 expression were observed in the hearts of other mouse strains, in heart tissues of patients with cardiomyopathy, and in human induced pluripotent stem cell-derived cardiomyocytes in which we also confirmed such posttranscriptional regulation of transgene expression. Our data clearly indicate that therapeutic utilization of miRNA-based regulation strategy needs to consider inter-individual variability.

| S-EPMC7270145 | biostudies-literature

Zinc dysregulation in cancers and its potential as a therapeutic target.

Project description:Zinc is an essential element and serves as a structural or catalytic component in many proteins. Two families of transporters are involved in maintaining cellular zinc homeostasis: the ZIP (SLC39A) family that facilitates zinc influx into the cytoplasm, and the ZnT (SLC30A) family that facilitates zinc efflux from the cytoplasm. Zinc dyshomeostasis caused by the dysfunction of zinc transporters can contribute to the initiation or progression of various cancers, including prostate cancer, breast cancer, and pancreatic cancer. In addition, intracellular zinc fluctuations lead to the disturbance of certain signaling pathways involved in the malignant properties of cancer cells. This review briefly summarizes our current understanding of zinc dyshomeostasis in cancer, and discusses the potential roles of zinc or zinc transporters in cancer therapy.

| S-EPMC7476080 | biostudies-literature

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential.

Project description:Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl- concentration ([Cl-]i) regulation impacts on both cell volume homeostasis and Cl--permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl-]i - cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl- transporters - could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl- cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl-]i and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl-]i that are relevant for two common clinical sequela of brain injury: edema and seizures.

| S-EPMC5473173 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data