MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55069 | GEO | 2014/02/18
SECONDARY ACCESSION(S): PRJNA238395
REPOSITORIES: GEO
Similar Datasets
Project description:MicroRNAs (miRNAs) have important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both human immunodeficiency virus (HIV)-associated dementia in humans and its monkey model simian immunodeficiency virus encephalitis (SIVE), we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. miR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 specifically targets the mRNA of myocyte enhancer factor 2C (MEF2C), a transcription factor crucial for neuronal function, and reduces its expression. MEF2C is dramatically downregulated in neurons of HIV-associated dementia patients, as well as monkeys with SIVE. Together, this study elucidates a novel role for miR-21 in the brain, not only as a potential signature of neurological disease, but also as a crucial effector of HIV-induced neuronal dysfunction and neurodegeneration. Total cellular RNA was isolated from frozen (−80°C) brain specimens by using TRIzol (Invitrogen, Carlsbad, CA, USA) for the monkey samples, and RNAzol (Biotecx Laboratories, Houston, TX, USA) for the human samples, followed by column purification (miRNeasy, Qiagen, Valencia, CA, USA) as per manufacture's instructions. For the monkeys, four samples were from uninfected animals and four from SIV-infected animals that developed simian AIDS with SIV encephalitis. For the human samples, six samples were from individuals who were HIV negative with no history of dementia or neurocognitive disability and showed no significant neuropathology. Five samples were from HIV positive individuals that were neurocognitively impaired (NNTC clinical rating >6)38 and a neuropathological diagnosis of HIV encephalitis. Clinical information is provided in the supplemental material. For microarray analysis, only three of the HAD specimens were sufficient for use, but all five were used for the qRT-PCR studies.
2014-02-18 | E-GEOD-55069 | biostudies-arrayexpress
Project description:The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, 1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.
2008-06-12 | E-GEOD-2377 | biostudies-arrayexpress
Project description:The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, 1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function. Keywords = HIV dementia Keywords = Gene array Keywords = Simian immunodeficiency virus Keywords = rhesus macaque Keywords: other
2005-03-08 | GSE2377 | GEO
Project description:Exosomes from the brains of rhesus macaques were isolated and characterized, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed that exosomes from the brains of animals with CNS disease contained significantly increased miR-21, a microRNA we have previously shown to be significantly increased in both SIV and HIV induced CNS disease. In addition to neurons in the brain, macrophage/microglial cells/nodules also express miR-21 during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into exosomes, and exosomes from macrophage cultures produced from WT, but not miR-21-/- KO, animals are neurotoxic. We find this neurotoxicity is dependent upon exosome carriage of miR-21, and mutation of the sequence within miR-21 predicted to bind TLR7 eliminates this neurotoxicity. Indeed exosomal miR-21 activates TLR7 in a reporter cell line, and the neurotoxicity of exosomal miR-21 is dependent upon TLR7, as neurons isolated from TLR7-/- KO mice are protected from neurotoxicity. Finally, we show that exosomes isolated from the brains of monkeys with SIV induced CNS disease both activate TLR7 and are neurotoxic when compared to exosomes from control animals.
2018-01-29 | GSE109414 | GEO
Project description:Human immunodeficiency virus 1 (HIV-1) infects blood monocytes that cross the blood-brain barrier to the central nervous system inducing neuronal damage. This damage is prompted by the secretion of viral and neurotoxic factors by HIV-infected macrophages and can result in HIV associated neurocognitive disorders (HAND). One of these neurotoxic factors secreted by HIV-infected macrophages is cathepsin B (CATB), a lysosomal cysteine protease that plays an important role in neurodegeneration. CATB interacts with Serum Amyloid P component (SAPC) contributing to HIV-induced neurotoxicity. However, the neuronal apoptosis pathways triggered by CATB and SAPC remain unknown. We aimed to elucidate these pathways in neurons exposed to HIV-infected macrophage conditioned media (MCM) before and after inhibition of CATB or SAPC using Tandem Mass Tag (TMT) proteomics labeling. Based on significant fold change (FC) ≥ ǀ2ǀ and p-value < 0.05 criteria, a total of 10, 48 and 13 proteins were deregulated after inhibiting CATB, SAPC antibodies and the cathepsin B inhibitor CA-074, respectively. We found that antibodies against CATB and SAPC, as well as the CATB inhibitor CA-074 downregulated apoptosis related proteins. CATB, SAPC or apoptotic related proteins could become potential targets against HIV-induced neuronal degeneration.
2022-01-20 | PXD024636 | Pride
Project description:The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNa nor IFN? are elevated in the brain, IL6 is increased. Both IFNa and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNa and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences. Keywords = HIV dementia Keywords = Gene array Keywords = Cytokine Keywords = Simian immunodeficiency virus Keywords: other
2005-03-10 | GSE2393 | GEO
Project description:Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Human fetal neurons were chosen to examine the impact of HIV-1 Tat protein on gene expression
2012-12-07 | E-GEOD-42423 | biostudies-arrayexpress
Project description:Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release from the infected cells and taken up by noninfected cells. Using microRNA array assay, we demonstrated that Tat deregulates the levels of several miRNAs. Interestingly, miR-34a was among the most highly induced miRNAs in Tat-treated neurons. Tat also decreases the levels of miR-34a target genes such as CREB protein as shown by real time PCR. The effect of Tat was neutralized in the presence of anti-miR-34a. Using in situ hybridization assay, we found that the levels of miR-34a increase in Tat transgenic mice when compared with the parental mice. Therefore, we conclude that deregulation of neuronal functions by HIV-1 Tat protein is miRNA-dependent. Human neurons SH-SY5Y were chosen to examine the impact of HIV-1 Tat protein on gene expression
2013-01-17 | E-GEOD-43534 | biostudies-arrayexpress
Project description:This project will help us to have a more accurate and useful explanation at molecular level, of the damage caused by HIV when it infects the central nervous sythem (CNS) in Humans. CNS dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus-I (HIV-1) infection and the acquired immunodeficiency virus syndrome (AIDS). Minor cognitive/motor dysfunction (MCMD) and HIV-1-associated dementia (HAD) develop in the absence of opportunistic infections and lymphoma, cerebrovascular disease and metabolic disorders. Patients with HAD may or may not present an associated HIV encephalitis with viral replication limited to cells of monocyte origin. The inflammatory infiltrates of HIVE include activated microglia and perivascular and parenchymal monocytes, multinucleated giant cells and lymphocytes. In addition, HIVE may be accompanied by significant loss of neurons, presynaptic terminals and abnormal dendrites. To determine if altered expression of neuronal growth factor, chemokine and cell death genes identified possible mechanisms of brain injury in AIDS patients with and without HIVE; Changes of gene expression occurring in brain of AIDS patients with and without HIVE, induce development of brain atrophy, mild gliosis, enhanced vascular permeability, along with alterations in neuronal HIV-1 chemokine coreceptors. In the cases of HIVE more remarkable gene expression changes result in significant loss of neurons, presynaptic terminals and abnormal dendrites. All these changes can be evaluated by microarray gene expression analysis and validated by Q-RT-PCR; The procedure includes 10 steps: 1-Frontal Cortex dissection from fresh frozen autopsy human brain samples (fragments of 0.8-1 cm3 are used) 2-totalRNA extraction using RNeasy Maxi Kit and following hand book protocol; Quiagen Inc., 3-RNA quantity determination using the NanoDrop ND-1000 UV-Vis Spectrophotometer: Nanodrop-Technologies 4-RNA quality analyzed by ribosomal fractions 28s/18s ratio, using by Agilent RNA 6000 Assay Microchips: Agilent Technologies 5-mRNA suitability by RT-PCR test for housekeeping genes and genes of interest. 6-mRNA amplification and labeling in two steps: a-Generation of T7-conatining double stranded cDNA using T7-Poly-T Strategy (Invitrogen) b-mRNA amplification and labeling (aRNA) by in vitro transcription using T7 RNA polymerase, T7-cDNA as template and biotin-labeled ribonucleotides 7-Biotin-labeled aRNA quantity assess, as in step 3 8-Biotin-labeled aRNA determination by amplified RNA electropherogram. Agilent RNA 6000 Assay Microchips: Agilent Technologies 9-Biotin-labeled aRNA fractionation, hybridization onto HG-95aVer2 oligonucleotide array and scanning, using Affymetrix platform: Affymetrix 10-Statistical gene expression analysis: Using GeneSpring Software (Slicon Gnetics) a-Normalization to the 50th percentile and per gene to specific control samples, using 'Disease vs. Normal' as the main parameter. b-Fold of expression filter (2 folds cutoff) using signal data in ratio mode interpretation c-Welch t-test, with p< 0.05 for significance, using log of ratio mode interpretation d-Differentially expressed genes clustering by K-means, experiment and gene trees e-Differentially expressed genes analysis and classes classification by Gene Ontology and GeneMapp pathways
2008-06-13 | E-GEOD-4755 | biostudies-arrayexpress
Project description:Finding the differences in gene expression in three regions of the brai, basal ganglia, white matter, and frontal cortex, in normal, HIV infected, HIV inefected with neurocognitive impairment, and HIV infected with both neurocognitive impairment and encephalitis patients. We used microarrays to identify differentially expressed genes in normal, HIV infected, HIV inefected with neurocognitive impairment, and HIV infected with both neurocognitive impairment and encephalitis patients. Samples from three different brain regions from normal, HIV infected, HIV infected with neurocognitive impairment (HAD: HIV-associated dementia), and HIV infected with both neurocognitive impairment and encephalitis (HIVE: HIV encephalitis) patients were collected for RNA isolation and supsequent Affymetrix microarray analysis. We sought to obtain gene expression levels in different brain regions to find implication of HIV and the neurological impairment and inflammation associated with HIV infection.
2012-07-31 | E-GEOD-35864 | biostudies-arrayexpress