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1.
Nucleic Acids Res ; 47(10): e59, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30869147

RESUMO

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.


Assuntos
Biologia Computacional/métodos , DNA Mitocondrial/genética , Transtorno Depressivo Maior/genética , Sítios de Splice de RNA/genética , Análise de Sequência de RNA/métodos , Deleção de Sequência , Algoritmos , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Quebras de DNA , DNA Mitocondrial/química , Transtorno Depressivo Maior/sangue , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase
2.
J Med Genet ; 51(3): 185-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24431331

RESUMO

INTRODUCTION: Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. METHODS AND RESULTS: Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. CONCLUSIONS: We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.


Assuntos
Anoftalmia/genética , Microftalmia/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Transdução de Sinais/genética , Tretinoína/metabolismo , Anoftalmia/fisiopatologia , Proliferação de Células , Células Cultivadas , Feminino , Fibroblastos , Humanos , Masculino , Microftalmia/fisiopatologia , Mutação/genética , Linhagem , Fenótipo , Sítios de Splice de RNA/genética
3.
J Neurosci ; 33(29): 11839-51, 2013 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-23864674

RESUMO

Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of 200 kb of linear sequence encompassing the GAD1 GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GAD1-TSS(-50kbLoop) was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GAD1-TSS(-50kbLoop) was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gad1-TSS(-55kbLoop), the murine homolog to GAD1-TSS(-50kbLoop), is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gad1-TSS(-55kbLoop) and Gad1 expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease.


Assuntos
Glutamato Descarboxilase/genética , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Animais , Antipsicóticos/farmacologia , Células Cultivadas , Cromossomos Humanos Par 2 , Clozapina/farmacologia , Metilação de DNA , Regulação para Baixo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Glutamato Descarboxilase/metabolismo , Haloperidol/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Esquizofrenia/metabolismo
4.
Commun Biol ; 7(1): 200, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368460

RESUMO

Common mitochondrial DNA (mtDNA) deletions are large structural variants in the mitochondrial genome that accumulate in metabolically active tissues with age and have been investigated in various diseases. We applied the Splice-Break2 pipeline (designed for high-throughput quantification of mtDNA deletions) to human RNA-Seq datasets and describe the methodological considerations for evaluating common deletions in bulk, single-cell, and spatial transcriptomics datasets. A robust evaluation of 1570 samples from 14 RNA-Seq studies showed: (i) the abundance of some common deletions detected in PCR-amplified mtDNA correlates with levels observed in RNA-Seq data; (ii) RNA-Seq library preparation method has a strong effect on deletion detection; (iii) deletions had a significant, positive correlation with age in brain and muscle; (iv) deletions were enriched in cortical grey matter, specifically in layers 3 and 5; and (v) brain regions with dopaminergic neurons (i.e., substantia nigra, ventral tegmental area, and caudate nucleus) had remarkable enrichment of common mtDNA deletions.


Assuntos
Encéfalo , Substância Negra , Humanos , RNA-Seq , Encéfalo/metabolismo , Substância Negra/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Mitocôndrias/genética
5.
Brain Behav Immun Health ; 36: 100731, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38435722

RESUMO

Objective: This study assessed the proteomic profiles of cytokines and chemokines in individuals with moderate to severe depression, with or without comorbid medical disorders, compared to healthy controls. Two proteomic multiplex platforms were employed for this purpose. Metods: An immunofluorescent multiplex platform and an aptamer-based method were used to evaluate 32 protein analytes from 153 individuals with moderate to severe major depressive disorder (MDD) and healthy controls (HCs). The study focused on determining the level of agreement between the two platforms and evaluating the ability of individual analytes and principal components (PCs) to differentiate between the MDD and HC groups. Additionally, the study investigated the relationship between PCs consisting of chemokines and cytokines and comorbid inflammatory and cardiometabolic diseases. Findings: Analysis revealed a small or moderate correlation between 47% of the analytes measured by the two platforms. Two proteomic profiles were identified that differentiated individuals with moderate to severe MDD from HCs. High eotaxin, age, BMI, IP-10, or IL-10 characterized profile 1. This profile was associated with several cardiometabolic risk factors, including hypertension, hyperlipidemia, and type 2 diabetes. Profile 2 is characterized by higher age, BMI, interleukins, and a strong negative loading for eotaxin. This profile was associated with inflammation but not cardiometabolic risk factors. Conclusion: This study provides further evidence that proteomic profiles can be used to identify potential biomarkers and pathways associated with MDD and comorbidities. Our findings suggest that MDD is associated with distinct profiles of proteins that are also associated with cardiometabolic risk factors, inflammation, and obesity. In particular, the chemokines eotaxin and IP-10 appear to play a role in the relationship between MDD and cardiometabolic risk factors. These findings suggest that a focus on the interplay between MDD and comorbidities may be useful in identifying potential targets for intervention and improving overall health outcomes.

6.
Nat Neurosci ; 27(7): 1387-1399, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38831039

RESUMO

Transcription factors (TFs) orchestrate gene expression programs crucial for brain function, but we lack detailed information about TF binding in human brain tissue. We generated a multiomic resource (ChIP-seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several postmortem brain regions, including binding maps for more than 100 TFs. We demonstrate improved measurements of TF activity, including motif recognition and gene expression modeling, upon identification and removal of high TF occupancy regions. Further, predictive TF binding models demonstrate a bias for these high-occupancy sites. Neuronal TFs SATB2 and TBR1 bind unique regions depleted for such sites and promote neuronal gene expression. Binding sites for TFs, including TBR1 and PKNOX1, are enriched for risk variants associated with neuropsychiatric disorders, predominantly in neurons. This work, titled BrainTF, is a powerful resource for future studies seeking to understand the roles of specific TFs in regulating gene expression in the human brain.


Assuntos
Encéfalo , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Encéfalo/metabolismo , Metilação de DNA , Neurônios/metabolismo , Sítios de Ligação , Ligação Proteica , Sequenciamento de Cromatina por Imunoprecipitação
7.
Complex Psychiatry ; 8(3-4): 90-98, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36778651

RESUMO

Introduction: Large somatic deletions of mitochondrial DNA (mtDNA) accumulate with aging in metabolically active tissues such as the brain. We have cataloged the breakpoints and frequencies of large mtDNA deletions in the human brain. Methods: We quantified 112 high-frequency mtDNA somatic deletions across four human brain regions with the Splice-Break2 pipeline. In addition, we utilized PLINK/Seq to test the association of mitochondrial genotypes with the abundance of these high-frequency mtDNA deletions. A conservative p value threshold of 5E-08 was used to find the significant loci. Results: One mtDNA SNP (T14798C) was significantly associated with mtDNA deletions in two brain regions, the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus. Since the DLPFC showed the most robust association between T14798C and two deletion breakpoints (7816-14807 and 5462-14807), this association was tested in the DLPFC of a replication sample and validated the first results. Incorporating the C allele at 14,798 bp increased the perfect/imperfect length of the repeat at the 3' breakpoint of the two associated deletions. Conclusion: This is the first study to identify the association of mtDNA SNP with large mtDNA deletions in the human brain. The T14798C allele located in the MT-CYB gene is a common polymorphism that occurs in several mitochondrial haplogroups. We hypothesize that the T14798C association with two deletions occurs by extending the repeat length around the 3' deletion breakpoints. This simple mechanism suggests that mtDNA SNPs can affect the mitochondrial genome structure, especially in brain where high levels of reactive oxygen species lead to deletion accumulation with aging.

8.
bioRxiv ; 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37873117

RESUMO

Transcription Factors (TFs) influence gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because genomic localization of TFs is in part driven by TF recognition of DNA sequence, variation in TF binding sites can disrupt TF-DNA associations and affect gene regulation. To identify variants that impact TF binding in human brain tissues, we quantified allele bias for 93 TFs analyzed with ChIP-seq experiments of multiple structural brain regions from two donors. Using graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signal between alleles at heterozygous variants within each tissue sample from each donor. Comparison of results from different brain regions within donors and the same regions between donors provided measures of allele bias reproducibility. We identified thousands of DNA variants that show reproducible bias in ChIP-seq for at least one TF. We found that alleles that are rarer in the general population were more likely than common alleles to exhibit large biases, and more frequently led to reduced TF binding. Combining ChIP-seq with RNA-seq, we identified TF-allele interaction biases with RNA bias in a phased allele linked to 6,709 eQTL variants identified in GTEx data, 3,309 of which were found in neural contexts. Our results provide insights into the effects of both common and rare variation on gene regulation in the brain. These findings can facilitate mechanistic understanding of cis-regulatory variation associated with biological traits, including disease.

9.
Transl Psychiatry ; 12(1): 159, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35422091

RESUMO

Suicides have increased to over 48,000 deaths yearly in the United States. Major depressive disorder (MDD) is the most common diagnosis among suicides, and identifying those at the highest risk for suicide is a pressing challenge. The objective of this study is to identify changes in gene expression associated with suicide in brain and blood for the development of biomarkers for suicide. Blood and brain were available for 45 subjects (53 blood samples and 69 dorsolateral prefrontal cortex (DLPFC) samples in total). Samples were collected from MDD patients who died by suicide (MDD-S), MDDs who died by other means (MDD-NS) and non-psychiatric controls. We analyzed gene expression using RNA and the NanoString platform. In blood, we identified 14 genes which significantly differentiated MDD-S versus MDD-NS. The top six genes differentially expressed in blood were: PER3, MTPAP, SLC25A26, CD19, SOX9, and GAR1. Additionally, four genes showed significant changes in brain and blood between MDD-S and MDD-NS; SOX9 was decreased and PER3 was increased in MDD-S in both tissues, while CD19 and TERF1 were increased in blood but decreased in DLPFC. To our knowledge, this is the first study to analyze matched blood and brain samples in a well-defined population of MDDs demonstrating significant differences in gene expression associated with completed suicide. Our results strongly suggest that blood gene expression is highly informative to understand molecular changes in suicide. Developing a suicide biomarker signature in blood could help health care professionals to identify subjects at high risk for suicide.


Assuntos
Transtorno Depressivo Maior , Suicídio , Sistemas de Transporte de Aminoácidos/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio , Transtorno Depressivo Maior/psicologia , Humanos , Córtex Pré-Frontal/metabolismo , Suicídio/psicologia
10.
Transl Psychiatry ; 12(1): 353, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042222

RESUMO

Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.


Assuntos
Transtorno Bipolar , Esquizofrenia , Transtorno Bipolar/metabolismo , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Feminino , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Esquizofrenia/metabolismo , Sinapses/metabolismo
11.
Sci Rep ; 10(1): 8626, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451470

RESUMO

The study of postsynaptic excitation to inhibition (E/I ratio) imbalances in human brain diseases, is a highly relevant functional measurement poorly investigated due to postmortem degradation of synaptic receptors. We show that near-simultaneous recording of microtransplanted synaptic receptors after simulated morgue conditions allows the determination of the postsynaptic E/I ratio for at least 120 h after death, expanding the availability and use of human diseased tissue stored in brain banks.


Assuntos
Encéfalo/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Adulto , Animais , Encefalopatias/patologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Humanos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Ácido Caínico/farmacologia , Masculino , Oócitos/citologia , Oócitos/metabolismo , Ratos , Ratos Wistar , Receptores de Neurotransmissores/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/fisiologia , Temperatura , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologia
12.
Am J Med Genet B Neuropsychiatr Genet ; 150B(7): 934-43, 2009 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-19152344

RESUMO

Altered stress reactivity is considered to be a risk factor for both major depressive disorder and suicidal behavior. The authors have sought to expand their previous findings implicating altered expression of spermidine/spermine N(1)-acetyltransferase 1 (SAT1), the rate-limiting enzyme involved in catabolism of the polyamines spermidine and spermine in the polyamine stress response (PSR), across multiple brain regions between control individuals and depressed individuals who have died by suicide. Microarray expression of probesets annotated to SAT1 were examined across 17 brain regions in 13 controls and 26 individuals who have died by suicide (16 with a diagnosis of major depression and 10 without), all of French-Canadian origin. Profiling conducted on the Affymetrix U133A/B chipset was further examined on a second chipset (U133 Plus 2.0) using RT-PCR, and analyzed in a second, independent sample. A reduction in SAT1 expression identified through multiple probesets was observed across 12 cortical regions in depressed individuals who have died by suicide compared with controls. Of these, five cortical regions showed statistically significant reductions which were supported by RT-PCR and analysis on the additional chipset. SAT1 cortical expression levels were also found to be significantly lower in an independent sample of German subjects with major depression who died by suicide in comparison with controls. These findings suggest that downregulation of SAT1 expression may play a role in depression and suicidality, possibly by impeding the normal PSR program or through compensation for the increased polyamine metabolism accompanying the psychological distress associated with depressive disorders.


Assuntos
Acetiltransferases/genética , Aciltransferases/genética , Encéfalo/metabolismo , Perfilação da Expressão Gênica , Suicídio/psicologia , Adulto , Estudos de Casos e Controles , Demografia , Depressão/genética , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Commun Biol ; 2: 153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069263

RESUMO

Altered expression of GABA receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAAR subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states. Here, by using microarray and RNA-Seq datasets-from single cell nuclei to global brain expression-from the Allen Institute, we find that transcriptional expression of GABAAR subunits is anatomically organized according to their neurodevelopmental origin. The data show a combination of complementary and mutually-exclusive expression patterns that delineate major isoforms, and which is highly stereotypical across brains from control donors. We summarize the region-specific signature of GABAR subunits per subject and its variability in a control population sample that can be used as a reference for remodeling changes during homeostatic rearrangements of GABAAR subunits after physiological, pharmacological or pathological challenges.


Assuntos
Encéfalo/metabolismo , Subunidades Proteicas/genética , Receptores de GABA-A/genética , Transcriptoma , Adulto , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/metabolismo , Encéfalo/anatomia & histologia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/metabolismo , Corpo Estriado/anatomia & histologia , Corpo Estriado/metabolismo , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Humanos , Hipotálamo/anatomia & histologia , Hipotálamo/metabolismo , Masculino , Mesencéfalo/anatomia & histologia , Mesencéfalo/metabolismo , Pessoa de Meia-Idade , Especificidade de Órgãos , Filogenia , Subunidades Proteicas/classificação , Subunidades Proteicas/metabolismo , Receptores de GABA-A/classificação , Receptores de GABA-A/metabolismo
15.
Cell Stem Cell ; 22(5): 698-712.e9, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29681516

RESUMO

The hypothalamus contains neurons that integrate hunger and satiety endocrine signals from the periphery and are implicated in the pathophysiology of obesity. The limited availability of human hypothalamic neurons hampers our understanding of obesity disease mechanisms. To address this, we generated human induced pluripotent stem cells (hiPSCs) from multiple normal body mass index (BMI; BMI ≤ 25) subjects and super-obese (OBS) donors (BMI ≥ 50) with polygenic coding variants in obesity-associated genes. We developed a method to reliably differentiate hiPSCs into hypothalamic-like neurons (iHTNs) capable of secreting orexigenic and anorexigenic neuropeptides. Transcriptomic profiling revealed that, although iHTNs maintain a fetal identity, they respond appropriately to metabolic hormones ghrelin and leptin. Notably, OBS iHTNs retained disease signatures and phenotypes of high BMI, exhibiting dysregulated respiratory function, ghrelin-leptin signaling, axonal guidance, glutamate receptors, and endoplasmic reticulum (ER) stress pathways. Thus, human iHTNs provide a powerful platform to study obesity and gene-environment interactions.


Assuntos
Grelina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Índice de Massa Corporal , Encéfalo/citologia , Encéfalo/metabolismo , Diferenciação Celular , Feminino , Humanos , Masculino , Obesidade Mórbida/genética , Transdução de Sinais/genética
16.
Mol Neuropsychiatry ; 3(3): 157-169, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29594135

RESUMO

Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA "common deletion" in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

17.
Biol Psychiatry ; 83(9): 780-789, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29628042

RESUMO

BACKGROUND: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. METHODS: We conducted gene-based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects. RESULTS: In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes. CONCLUSIONS: This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.


Assuntos
Genes Mitocondriais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Arch Gen Psychiatry ; 63(1): 35-48, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16389195

RESUMO

CONTEXT: A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors. OBJECTIVE: To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions. DESIGN: Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation. SUBJECTS: We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin. MAIN OUTCOME MEASURES: Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. RESULTS: Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P

Assuntos
Acetiltransferases/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Variação Genética , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Suicídio/estatística & dados numéricos , Acetiltransferases/metabolismo , Adulto , Western Blotting , Córtex Cerebral/metabolismo , Mapeamento Cromossômico , Análise por Conglomerados , Transtorno Depressivo Maior/diagnóstico , Perfilação da Expressão Gênica/estatística & dados numéricos , Predisposição Genética para Doença/psicologia , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Córtex Motor/metabolismo , Sondas de Oligonucleotídeos , Córtex Pré-Frontal/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suicídio/psicologia
19.
BMC Psychiatry ; 7: 9, 2007 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-17324276

RESUMO

BACKGROUND: Bipolar disorder (BD) is a major psychiatric condition that commonly requires prophylactic and episodic treatment. Lithium (Li) has been used for over 40 years now as an effective prophylactic agent. Response to Li treatment seems to be, at least in part, genetically determined. Although we ignore how Li specifically prevents mood episodes, it has previously been suggested that Li exerts an effect on the phosphoinositide pathway, and more recently, it has been proposed that Li may modulate prolyl endopeptidase (PREP). METHODS: In this study we carried out an association study looking at the PREP gene, located on ch 6q22. Five intronic single nucleotide polymorphisms (SNP), three coding SNPs and one SNP in the 5' UTR were investigated for their frequency in a BD sample of 180 excellent Li responders, 69 Li nonresponders and 126 controls. Genotyping was carried out using the SNaPshot reaction from Applied Biosystems, which is a modified fluorescent single base pair extension procedure. RESULTS: Following correction for multiple testing, no significant genotypic, allelic or estimated haplotypic differences were found between responders and nonresponders or between BD patients and controls. CONCLUSION: PREP is an interesting candidate gene to investigate in genetic studies of BD, but our findings do not support the hypothesis that genetic variation in this gene plays a major role in the etiology of BD or Li response.


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Carbonato de Lítio/uso terapêutico , Serina Endopeptidases/genética , Adulto , Afeto/efeitos dos fármacos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prolil Oligopeptidases
20.
OMICS ; 10(4): 444-54, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17233556

RESUMO

Microarrays offer the possibility of screening in parallel virtually all genes expressed in a given tissue or to study the molecular signature associated with available treatments. As such, this technology has been increasingly used to investigate multifactorial and polygenic complex traits such as psychiatric disorders, in particular, schizophrenia and mood disorders. This review focuses on microarray studies investigating mood disorders. Study designs, methodologic approaches and limitations, subsequent follow-up strategies, and confirmation of results are discussed. Despite the apparent disparate and not always concordant results, it appears evident that this technology is a powerful and inevitable approach for the study of mood disorders, especially when phenotype-specific confounders are properly accounted for. Thus, alterations of mitochondrial, oligodendrocyte, and myelin related genes in bipolar disorder, of signaling and olidendroglial related genes in depression, and of GABA-glutamate related genes in depression and suicide have been observed and have confirmed new avenues for the study and the treatment of these complex disorders.


Assuntos
Perfilação da Expressão Gênica , Genoma Humano/fisiologia , Transtornos do Humor/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
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