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BACKGROUND: For more than 16 years, we have selectively bred rats for either high or low levels of exploratory activity within a novel environment. These bred high-responder (bHR) and bred low-responder (bLR) rats model temperamental extremes, exhibiting large differences in internalizing and externalizing behaviors relevant to mood and substance use disorders. METHODS: We characterized persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation, by meta-analyzing 8 transcriptional profiling datasets (microarray and RNA sequencing) spanning 43 generations of selective breeding (postnatal day 7: n = 22; postnatal day 14: n = 49; postnatal day 21: n = 21; adult: n = 46; all male). We cross-referenced expression differences with exome sequencing within our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype. The results were compared with hippocampal profiling from other bred rat models. RESULTS: Genetic and transcriptional profiling results converged to implicate multiple candidate genes, including two previously associated with metabolism and mood: Trhr and Ucp2. Results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, centering on Bmp4 and Mki67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including 2 genes within implicated chromosomal regions: C1qa and Mfge8. CONCLUSIONS: These candidate genes and functional pathways may direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.
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Ansiedad , Hipocampo , Animales , Antígenos de Superficie , Depresión , Conducta Exploratoria , Masculino , Proteínas de la Leche , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Emerging evidence suggests that the spread of glioma to the subventricular zone (SVZ) is closely related to glioma recurrence and patient survival. Neural stem cells (NSCs) are the main cell type in the SVZ region and exhibit tumor-homing ability. AIM: To evaluate the effects of conditioned medium (CM) derived from SVZ NSCs on the cancer-related behaviors of glioma cells. METHODS: The characteristics of SVZ hNSCs were identified by immunofluorescence. The normoxic-hNSC-CM and hypoxic-hNSC-CM (3% O2, oxygen-glucose deprived [OGD] culturing) were collected from 80%-90% confluent SVZ NSCs in sterile conditions. The CCK8 and Transwell assays were used to compare and evaluate the effects of normoxic-CM and hypoxic-CM on glioma proliferation and invasion. Then proteins secreted from SVZ NSCs into the CM were investigated by mass spectrometry, and the potential effects of candidate protein NCAN in the regulation of glioma progression were examined by CCK8 and Transwell assays. RESULTS: The CM from SVZ NSCs significantly increased the proliferation and invasion of glioma cells, particularly the CM from OGD NSCs induced under hypoxic conditions. Furthermore, the secreted protein neurocan (NCAN) in CM from OGD NSCs was identified by proteomic analysis. NCAN was expressed in glioma cells and played regulatory roles in mediating the progression of glioma cells mainly via the Rho/Rho-associated protein kinase pathway. CONCLUSION: Our study identified a potential interactive mechanism between SVZ NSCs and glioma cells, in which SVZ NSCs promote glioma progression via the secreted protein NCAN. These findings suggested that exploring the CM derived from cells could be a novel strategy for optimizing treatments and that NCAN derived from SVZ NSCs may be a potential new target in glioma progression.
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BACKGROUND: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. METHODS: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. RESULTS: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. CONCLUSIONS: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.
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Trastorno Bipolar/genética , Células-Madre Neurales/metabolismo , Organoides/metabolismo , Transcriptoma , Adulto , Trastorno Bipolar/metabolismo , Adhesión Celular , Células Cultivadas , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Potenciales de la Membrana , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Neurocano , Organoides/citología , Organoides/fisiologíaRESUMEN
Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease-relevant mechanisms. Building on our recent work showing the association of clinical disease course with post-mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology-associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T-allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.
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Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Autopsia/métodos , Encéfalo/patología , Antígeno CTLA-4/genética , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Sustancia Gris/patología , Humanos , Proteínas de Interacción con los Canales Kv/genética , Lectinas Tipo C/genética , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Monosacáridos/genética , Oligodendroglía/patología , Receptor fas/genéticaRESUMEN
Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 × 10-9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders.
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Neurocan (NCAN), a secreted chondroitin sulfate proteoglycan, is one of the major inhibitory molecules for axon regeneration in nervous injury. However, its role in cancer is not clear. Here we observed that high NCAN expression was closely associated with the unfavorable outcome of neuroblastoma (NB). NCAN was also highly and ubiquitously expressed in the early lesions and terminal tumor of TH-MYCN mice, a NB model. Interestingly, exogenous NCAN (i.e., overexpression, recombinant protein and conditioned medium) transformed adherent NB cells into spheres whose malignancies in vitro (anchorage-independent growth and chemoresistance) and in vivo (xenograft tumor growth) were potentiated. Both chondroitin sulfate sugar chains and NCAN's core protein were essential for the sphere formation. The CSG3 domain was essential in the moiety of NCAN. Our comprehensive microarray analysis and RT-qPCR of mRNA expression suggested that NCAN treatment promoted cell division, and urged cells to undifferentiated state. The knockdown of NCAN in tumor sphere cells cultured from TH-MYCN mice resulted in growth suppression in vitro and in vivo. Our findings suggest that NCAN, which stimulates NB cells to promote malignant phenotypes, is an extracellular molecule providing a growth advantage to cancer cells.
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BACKGROUND: Recently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population. METHODS: Gene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques. RESULTS: No significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P > 0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P = 0.017) and a higher high-density lipoprotein (HDL) (P < 0.05). CONCLUSIONS: Our study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP. TRIAL REGISTRATION: Chinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447 .
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Proteoglicanos Tipo Condroitín Sulfato/genética , Predisposición Genética a la Enfermedad , Lectinas Tipo C/genética , Proteínas del Tejido Nervioso/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Polimorfismo de Nucleótido Simple , Adulto , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Humanos , Incidencia , Lipoproteínas HDL/sangre , Lipoproteínas HDL/genética , Masculino , Persona de Mediana Edad , Neurocano , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN), is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia. METHODS: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction) and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction). CONCLUSION: Our findings indicate that this single nucleotide polymorphism may be a risk factor for cognitive dysfunction in patients with schizophrenia. Further investigations are warranted for validation purposes and to identify the precise mechanism by which rs1064395 influences cognitive performance in patients with schizophrenia.
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Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.
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The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.
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Trastorno Bipolar/genética , Trastorno Bipolar/fisiopatología , Encéfalo/fisiopatología , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Ancirinas/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Trastorno Bipolar/psicología , Canales de Calcio Tipo L/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Femenino , Neuroimagen Funcional , Genes , Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/psicología , Genoma , Estudio de Asociación del Genoma Completo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Lectinas Tipo C/genética , Masculino , Mutación/genética , Proteínas del Tejido Nervioso/genética , Neurocano , Neurogranina/genética , Fenotipo , Polimorfismo Genético , Trastornos Psicóticos/fisiopatología , Factores de Riesgo , Psicología del Esquizofrénico , Factor de Transcripción 4 , Factores de Transcripción/genéticaRESUMEN
The A allele of the single nucleotide polymorphism (SNP) rs1064395 in the NCAN gene has recently been identified as a susceptibility factor for bipolar disorder and schizophrenia. NCAN encodes neurocan, a brain-specific chondroitin sulfate proteoglycan that is thought to influence neuronal adhesion and migration. Several lines of research suggest an impact of NCAN on neurocognitive functioning. In the present study, we investigated the effects of rs1064395 genotype on neural processing and cognitive performance in healthy subjects. Brain activity was measured with functional magnetic resonance imaging (fMRI) during an overt semantic verbal fluency task in 110 healthy subjects who were genotyped for the NCAN SNP rs1064395. Participants additionally underwent comprehensive neuropsychological testing. Whole brain analyses revealed that NCAN risk status, defined as AA or AG genotype, was associated with a lack of task-related deactivation in a large left lateral temporal cluster extending from the middle temporal gyrus to the temporal pole. Regarding neuropsychological measures, risk allele carriers demonstrated poorer immediate and delayed verbal memory performance when compared to subjects with GG genotype. Better verbal memory performance was significantly associated with greater deactivation of the left temporal cluster during the fMRI task in subjects with GG genotype. The current data demonstrate that common genetic variation in NCAN influences both neural processing and cognitive performance in healthy subjects. Our study provides new evidence for a specific genetic influence on human brain function.
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Mapeo Encefálico , Encéfalo/fisiología , Proteoglicanos Tipo Condroitín Sulfato/genética , Cognición/fisiología , Lectinas Tipo C/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Encéfalo/irrigación sanguínea , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Voluntarios Sanos , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Neurocano , Pruebas Neuropsicológicas , Oxígeno/sangre , Esquizofrenia , Aprendizaje Verbal , Adulto JovenRESUMEN
BACKGROUND & AIMS: The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). METHODS: We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy. RESULTS: The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver. CONCLUSIONS: NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.
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Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Lectinas Tipo C/genética , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/genética , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Anciano de 80 o más Años , Alcoholismo/genética , Estudios de Casos y Controles , Línea Celular , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Células Hep G2 , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/genética , Hepatocitos/metabolismo , Humanos , Cirrosis Hepática Alcohólica/genética , Masculino , Persona de Mediana Edad , Neurocano , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND & AIMS: A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. METHODS: We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. RESULTS: The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. CONCLUSIONS: We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.