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Jesus A Garciasevilla - One of the best experts on this subject based on the ideXlab platform.
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regulation of munc18 1 and syntaxin 1a interactive partners in schizophrenia prefrontal cortex down regulation of munc18 1a isoform and 75 kda snare complex after antipsychotic treatment
The International Journal of Neuropsychopharmacology, 2012Co-Authors: Itziar Gilpisa, Eva Munarrizcuezva, Alfredo Ramosmiguel, Leyre Uriguen, Javier J Meana, Jesus A GarciasevillaAbstract:Munc18-1 and syntaxin-1 are crucial interacting molecules for synaptic membrane fusion and neurotransmitter release. Contrasting abnormalities of several proteins of the exocytotic machinery, including the formation of SNARE (synaptobrevin, SNAP-25 and syntaxin-1) complexes, have been reported in schizophrenia. This study quantified in the dorsolateral prefrontal cortex (PFC, Brodmann Area 9) the immunocontent of munc18-1a/b isoforms, syntaxin-1A, other presynaptic proteins (synaptotagmin, synaptophysin), and SNARE complexes, as well as the effects of psychoactive drug exposure, in schizophrenia (SZ, n=24), non-schizophrenia suicide (SD, n=13) and major depression (MD, n=15) subjects compared to matched controls (n=39). SZ was associated with normal expression of munc18-1a/b and increased syntaxin-1A (+44 %). The presence of antipsychotic drugs reduced the basal content of munc18-1a isoform (x23 %) and synaptobrevin (x32 %), and modestly reduced that of up-regulated syntaxin-1A (x16 %). Munc18-1a and syntaxin-1A protein expression correlated positively in controls but showed a markedly opposite pattern in SZ, regardless of antipsychotic treatment. Thus, the ratio of syntaxin-1A to munc18-1a showed a net increase in SZ (+53/114 %). The SNARE complex (75 kDa) was found unaltered in antipsychotic-free and reduced (x28 %) in antipsychotic-treated SZ subjects. None of these abnormalities were observed in SD and MD subjects, unexposed or exposed to psychoactive drugs. The results reveal some exocytotic dysfunctions in SZ that are probably related to an imbalance of the interaction between munc18-1a and SNARE (mainly syntaxin-1A) complex. Moreover, antipsychotic drug treatment is associated with lower content of key proteins of the exocytotic machinery, which could result in a destabilization/impairment of neurosecretion.
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opposite age dependent changes of α2a adrenoceptors and nonadrenoceptor 3h idazoxan binding sites i2 imidazoline sites in the human brain strong correlation of i2 with monoamine oxidase b sites
Journal of Neurochemistry, 1993Co-Authors: Magdalena Sastre, Jesus A GarciasevillaAbstract:: In the postmortem human brain (27 specimens of frontal cortex, Brodmann Area 9), the specific binding of the antagonists [3H]RX 821002 (2-methoxyidazoxan) to α2A-adrenoceptors and that of [3H]idazoxan to l2-imidazo-line sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4–89 years) on both brain proteins. The density of α2A-adrenoceptors and age were negatively correlated (r=-0.71; p < 0.001). In contrast, the density of l2-imidazo-line sites was positively correlated with aging (r= 0.59; p < 0.005). The ratio of receptor densities (α2A/l2) also showed a marked negative correlation with age (r=-0.76; p < 0.001). In an age-selected group (range, 10–89 years), the density of monoamine oxidase (MAO)-B sites labeled by [3H]Ro 19–6327 (lazabemide) also showed a positive correlation with age (r= 0.80; p < 0.005). In these subjects, the density of l2-imidazoline sites correlated well with the density of MAO-B sites (r= 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/l2) did not correlate with the age of the subject at death (r=-0.15). In the human frontal cortex, idazoxan displayed very low affinity (Ki= 89 μM) against the binding of [3H]Ro 19–6327 to MAO-B, which discounted a direct interaction of [3H]idazoxan with the active center of the enzyme and indicated that the l2-imidazoline site cannot be identified with MAO-B. However, l2-imidazoline sites and MAO-B show a clear coexpression not only in the human frontal cortex during the process of aging, but also in various brain regions of the human and rat brains. It is suggested that the l2-imidazoline site has a specific location on glial (astrocyte) cells.
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opposite age dependent changes of alpha 2a adrenoceptors and nonadrenoceptor 3h idazoxan binding sites i2 imidazoline sites in the human brain strong correlation of i2 with monoamine oxidase b sites
Journal of Neurochemistry, 1993Co-Authors: Magdalena Sastre, Jesus A GarciasevillaAbstract:In the postmortem human brain (27 specimens of frontal cortex, Brodmann Area 9), the specific binding of the antagonists [3H]RX 821002 (2-methoxyidazoxan) to alpha 2A-adrenoceptors and that of [3H]idazoxan to I2-imidazoline sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4-89 years) on both brain proteins. The density of alpha 2A-adrenoceptors and age were negatively correlated (r = -0.71; p < 0.001). In contrast, the density of I2-imidazoline sites was positively correlated with aging (r = 0.59; p < 0.005). The ratio of receptor densities (alpha 2A/I2) also showed a marked negative correlation with age (r = -0.76; p < 0.001). In an age-selected group (range, 10-89 years), the density of monoamine oxidase (MAO)-B sites labeled by [3H]Ro 19-6327 (lazabemide) also showed a positive correlation with age (r = 0.80; p < 0.005). In these subjects, the density of I2-imidazoline sites correlated well with the density of MAO-B sites (r = 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/I2) did not correlate with the age of the subject at death (r = -0.15). In the human frontal cortex, idazoxan displayed very low affinity (Ki = 89 microM) against the binding of [3H]Ro 19-6327 to MAO-B, which discounted a direct interaction of [3H]idazoxan with the active center of the enzyme and indicated that the I2-imidazoline site cannot be identified with MAO-B.(ABSTRACT TRUNCATED AT 250 WORDS)
Magdalena Sastre - One of the best experts on this subject based on the ideXlab platform.
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opposite age dependent changes of α2a adrenoceptors and nonadrenoceptor 3h idazoxan binding sites i2 imidazoline sites in the human brain strong correlation of i2 with monoamine oxidase b sites
Journal of Neurochemistry, 1993Co-Authors: Magdalena Sastre, Jesus A GarciasevillaAbstract:: In the postmortem human brain (27 specimens of frontal cortex, Brodmann Area 9), the specific binding of the antagonists [3H]RX 821002 (2-methoxyidazoxan) to α2A-adrenoceptors and that of [3H]idazoxan to l2-imidazo-line sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4–89 years) on both brain proteins. The density of α2A-adrenoceptors and age were negatively correlated (r=-0.71; p < 0.001). In contrast, the density of l2-imidazo-line sites was positively correlated with aging (r= 0.59; p < 0.005). The ratio of receptor densities (α2A/l2) also showed a marked negative correlation with age (r=-0.76; p < 0.001). In an age-selected group (range, 10–89 years), the density of monoamine oxidase (MAO)-B sites labeled by [3H]Ro 19–6327 (lazabemide) also showed a positive correlation with age (r= 0.80; p < 0.005). In these subjects, the density of l2-imidazoline sites correlated well with the density of MAO-B sites (r= 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/l2) did not correlate with the age of the subject at death (r=-0.15). In the human frontal cortex, idazoxan displayed very low affinity (Ki= 89 μM) against the binding of [3H]Ro 19–6327 to MAO-B, which discounted a direct interaction of [3H]idazoxan with the active center of the enzyme and indicated that the l2-imidazoline site cannot be identified with MAO-B. However, l2-imidazoline sites and MAO-B show a clear coexpression not only in the human frontal cortex during the process of aging, but also in various brain regions of the human and rat brains. It is suggested that the l2-imidazoline site has a specific location on glial (astrocyte) cells.
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opposite age dependent changes of alpha 2a adrenoceptors and nonadrenoceptor 3h idazoxan binding sites i2 imidazoline sites in the human brain strong correlation of i2 with monoamine oxidase b sites
Journal of Neurochemistry, 1993Co-Authors: Magdalena Sastre, Jesus A GarciasevillaAbstract:In the postmortem human brain (27 specimens of frontal cortex, Brodmann Area 9), the specific binding of the antagonists [3H]RX 821002 (2-methoxyidazoxan) to alpha 2A-adrenoceptors and that of [3H]idazoxan to I2-imidazoline sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4-89 years) on both brain proteins. The density of alpha 2A-adrenoceptors and age were negatively correlated (r = -0.71; p < 0.001). In contrast, the density of I2-imidazoline sites was positively correlated with aging (r = 0.59; p < 0.005). The ratio of receptor densities (alpha 2A/I2) also showed a marked negative correlation with age (r = -0.76; p < 0.001). In an age-selected group (range, 10-89 years), the density of monoamine oxidase (MAO)-B sites labeled by [3H]Ro 19-6327 (lazabemide) also showed a positive correlation with age (r = 0.80; p < 0.005). In these subjects, the density of I2-imidazoline sites correlated well with the density of MAO-B sites (r = 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/I2) did not correlate with the age of the subject at death (r = -0.15). In the human frontal cortex, idazoxan displayed very low affinity (Ki = 89 microM) against the binding of [3H]Ro 19-6327 to MAO-B, which discounted a direct interaction of [3H]idazoxan with the active center of the enzyme and indicated that the I2-imidazoline site cannot be identified with MAO-B.(ABSTRACT TRUNCATED AT 250 WORDS)
Victoria Arango - One of the best experts on this subject based on the ideXlab platform.
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whole transcriptome brain expression and exon usage profiling in major depression and suicide evidence for altered glial endothelial and atpase activity
Molecular Psychiatry, 2017Co-Authors: Spiro P Pantazatos, Victoria Arango, Gorazd Rosoklija, Yungyu Huang, Andrew J Dwork, John J MannAbstract:Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood-brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.
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region specific alterations of a to i rna editing of serotonin 2c receptor in the cortex of suicides with major depression
Translational Psychiatry, 2016Co-Authors: Dinah Weissmann, Sieger Van Der Laan, Nicolas Salvetat, Laurent Cavarec, Laurent Vincent, Franck Molina, J J Mann, Mark D Underwood, Victoria Arango, J F PujolAbstract:Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical Areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann Area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical Areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical Area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide.
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glucocorticoid receptor related genes genotype and brain gene expression relationships to suicide and major depressive disorder
Depression and Anxiety, 2016Co-Authors: Victoria Arango, M Honglei D Yin, Hanga Galfalvy, Spiro P Pantazatos, M Yungyu S Huang, Gorazd Rosoklija, J Andrew M D Dwork, Ainsley K Burke, Maria A OquendoAbstract:INTRODUCTION: We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1). MATERIALS AND METHODS: Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). RESULTS: We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P =.014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P =.004). CONCLUSION: We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior.© 2016 Wiley Periodicals, Inc. Language: en
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isoform level brain expression profiling of the spermidine spermine n1 acetyltransferase1 sat1 gene in major depression and suicide
Neurobiology of Disease, 2015Co-Authors: Spiro P Pantazatos, Victoria Arango, Yungyu Huang, Stuart J Andrews, Jane Dunningbroadbent, Jiuhong Pang, Peter L Nagy, John J MannAbstract:Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N = 29), DSM-IV major depressive disorder suicides (MDD-S, N = 21) and MDD non-suicides (MDD, N = 9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p = 0.002) and MDD (vs. HC, p = 0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) were pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p < 0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expressions of both SSAT and SATX isoforms suggest that shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide.
Adam Labadorf - One of the best experts on this subject based on the ideXlab platform.
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the caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal huntington s disease brain
BMC Medical Genomics, 2019Co-Authors: Filisia Agus, Diego Crespo, Richard H Myers, Adam LabadorfAbstract:The mechanisms underlying neurodegeneration in the striatum of Huntingon’s Disease (HD) brain are currently unknown. While the striatum is massively degenerated in symptomatic individuals, which makes cellular characterization difficult, it is largely intact in asymptomatic HD gene positive (HD+) individuals. Unfortunately, as striatal tissue samples from HD+ individuals are exceedingly rare, recent focus has been on the Brodmann Area 9 (BA9), a relatively unaffected region, as a surrogate tissue. In this study, we analyze gene expression in caudate nucleus (CAU) from two HD+ individuals and compare the results with healthy and symptomatic HD brains. High-throughput mRNA sequencing (mRNA-Seq) datasets were generated from post-mortem CAU of 2 asymptomatic HD+ individuals and compared with 26 HD and 56 neurologically normal controls. Datasets were analyzed using a custom bioinformatic analysis pipeline to identify and interpret differentially expressed (DE) genes. Results were compared to publicly available brain mRNA-Seq datasets from the Genotype-Tissue Expression (GTEx) project. The analysis employed current state of the art bioinformatics tools and tailored statistical and machine learning methods. The transcriptional profiles in HD+ CAU and HD BA9 samples are highly similar. Differentially expressed (DE) genes related to the heat shock response, particularly HSPA6 and HSPA1A, are common between regions. The most perturbed pathways show extensive agreement when comparing disease with control. A random forest classifier predicts that the two HD+ CAU samples strongly resemble HD BA9 and not control BA9. Nonetheless, when genes were prioritized by their specificity to HD+ CAU, pathways spanning many biological processes emerge. Comparison of HD+ BA9 with HD BA9 identified NPAS4 and REST1/2 as potential early responders to disease and reflect the active disease process. The caudate nucleus in HD brain is dramatically affected prior to symptom onset. Gene expression patterns observed in the HD BA9 are also present in the CAU, suggesting a common response to disease. Substantial caudate-specific differences implicate many different biological pathways including metabolism, protein folding, inflammation, and neurogenic processes. While these results are at best trends due to small sample sizes, these results nonetheless provide the most detailed insight to date into the primary HD disease process.
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the caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal huntington s disease brain
bioRxiv, 2019Co-Authors: Filisia Agus, Diego Crespo, Richard H Myers, Adam LabadorfAbstract:ABSTRACT The mechanisms underlying degeneration of the specific neurons in the striatum of Huntingon’s Disease (HD) brain are currently unknown. The striatum is massively degenerated in late stage HD, making examination of post-mortem brain tissue from symptomatic individuals problematic. Striatal tissue is largely intact in the brains of asymptomatic HD positive (HD+) gene carriers, but these samples are exceedingly rare. In this study, caudate nucleus (CAU) tissue from two asymptomatic HD+ individuals was subjected to high throughput mRNA sequencing (mRNA-Seq) for comparison with similar datasets from symptomatic HD individuals and healthy controls. The overall transcriptional response in HD+ CAU shares much of the same response observed in HD Brodmann Area 9 (BA9) samples, an Area that is relatively spared from significant degeneration. A set of differentially expressed (DE) genes predominantly related to the heat shock response are found in common between brain regions, and show much higher induction in HD+ CAU than HD BA9. The most highly perturbed pathways show near complete agreement when comparing diseased tissue with control, and a random forest classifier predicted that the two HD+ CAU samples strongly resemble HD BA9 and not control BA9. Nonetheless, when genes were prioritized by their specificity to HD+ CAU, a large number of pathways spanning many biological processes emerged. Further comparison of HD+ BA9 with HD BA9 identified genes that may be early responders to disease, and have altered expression in symptomatic individuals. This study presents the first and largest examination of asymptomatic brain gene expression to date, and suggests many new avenues of investigation into the mechanisms underlying neurodegeneration in HD.
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mir 10b 5p expression in huntington s disease brain relates to age of onset and the extent of striatal involvement
BMC Medical Genomics, 2015Co-Authors: Andrew G Hoss, Adam Labadorf, Vinay K Kartha, Jeanne C Latourelle, Tiffany C Hadzi, Marcy E Macdonald, James F Gusella, Schahram Akbarian, Jiangfan Chen, Zhiping WengAbstract:Background: MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. Methods: We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. Results: We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation. Conclusions: These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD.
Spiro P Pantazatos - One of the best experts on this subject based on the ideXlab platform.
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whole transcriptome brain expression and exon usage profiling in major depression and suicide evidence for altered glial endothelial and atpase activity
Molecular Psychiatry, 2017Co-Authors: Spiro P Pantazatos, Victoria Arango, Gorazd Rosoklija, Yungyu Huang, Andrew J Dwork, John J MannAbstract:Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood-brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.
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glucocorticoid receptor related genes genotype and brain gene expression relationships to suicide and major depressive disorder
Depression and Anxiety, 2016Co-Authors: Victoria Arango, M Honglei D Yin, Hanga Galfalvy, Spiro P Pantazatos, M Yungyu S Huang, Gorazd Rosoklija, J Andrew M D Dwork, Ainsley K Burke, Maria A OquendoAbstract:INTRODUCTION: We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1). MATERIALS AND METHODS: Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). RESULTS: We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P =.014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P =.004). CONCLUSION: We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior.© 2016 Wiley Periodicals, Inc. Language: en
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isoform level brain expression profiling of the spermidine spermine n1 acetyltransferase1 sat1 gene in major depression and suicide
Neurobiology of Disease, 2015Co-Authors: Spiro P Pantazatos, Victoria Arango, Yungyu Huang, Stuart J Andrews, Jane Dunningbroadbent, Jiuhong Pang, Peter L Nagy, John J MannAbstract:Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N = 29), DSM-IV major depressive disorder suicides (MDD-S, N = 21) and MDD non-suicides (MDD, N = 9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p = 0.002) and MDD (vs. HC, p = 0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) were pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p < 0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expressions of both SSAT and SATX isoforms suggest that shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide.
