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Effect of paraquat and nicotine on gene expression in a Drosophila melanogaster Parkinson's disease model

ABSTRACT: Cigarette smoking is associated with reduced risk of developing Parkinson’s disease (PD). To identify genes that interact with nicotine/smoking, we performed hypothesis-free genome-wide experiments in a paraquat-induced Drosophila model and in a case-control study of PD. We demonstrated that nicotine extends life-span in paraquat-treated Drosophila (P=4E-30). Brain tissue from flies treated with combinations of paraquat and nicotine revealed elevated expression of CG14691 with paraquat which was restored with nicotine co-treatment (P(interaction)=2E-11, P(FDR-adjusted)=4E-7). Independently, variants in the 5’ region of SV2C, a human ortholog of CG14691, gave the strongest signal for interaction with smoking (P(interaction)=9E-8). The effect of smoking on PD risk varied six-fold by SV2C genotype (P(heterogeneity)=4E-10). Moreover, SV2C variants identified here were associated with SVC2 gene-expression in the HapMap data. Present results suggest synaptic vesicle protein SV2C plays a role in PD pathogenesis, and that the SV2C genotype may be useful for clinical trials of nicotine for treating PD.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE35930 | GEO | 2012/09/05

SECONDARY ACCESSION(S): PRJNA152069

REPOSITORIES: GEO

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Effect of paraquat and nicotine on gene expression in a Drosophila melanogaster Parkinson's disease model

Project description:Cigarette smoking is associated with reduced risk of developing Parkinson’s disease (PD). To identify genes that interact with nicotine/smoking, we performed hypothesis-free genome-wide experiments in a paraquat-induced Drosophila model and in a case-control study of PD. We demonstrated that nicotine extends life-span in paraquat-treated Drosophila (P=4E-30). Brain tissue from flies treated with combinations of paraquat and nicotine revealed elevated expression of CG14691 with paraquat which was restored with nicotine co-treatment (P(interaction)=2E-11, P(FDR-adjusted)=4E-7). Independently, variants in the 5’ region of SV2C, a human ortholog of CG14691, gave the strongest signal for interaction with smoking (P(interaction)=9E-8). The effect of smoking on PD risk varied six-fold by SV2C genotype (P(heterogeneity)=4E-10). Moreover, SV2C variants identified here were associated with SVC2 gene-expression in the HapMap data. Present results suggest synaptic vesicle protein SV2C plays a role in PD pathogenesis, and that the SV2C genotype may be useful for clinical trials of nicotine for treating PD. Drosophila female heads were dissected after exposure to plain food, food with paraquat, food with nicotine, or food with both paraquat and nicotine, and genome-wide expression was quantified using Affymetrix microarrays. 20 heads were pooled per replicate, with each treatment in triplicate, and all flies were dissected at the same timepoint, after 10 days of pretreatment (with 0.1 mg/ml nicotine or no nicotine, depending on treatment group), and then a further 6 days of treatment with either 5 mM paraquat or no paraquat, continuing on the pretreatment dose of nicotine. One biological replicate in the paraquat-only group showed RNA degradation and was not included in the normalization or subsequent analyses.

2012-09-05 | E-GEOD-35930 | biostudies-arrayexpress

Gene expression of A53T and corrected IPSC driven to DA neurons and exposed to paraquat and maneb

Project description:Parkinson disease (PD) is characterized by extensive loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). A strong association has been reported between PD and exposure to mitochondrial toxins such as the environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived, stem cell model of PD that allows comparison of -synuclein ( -syn) mutant cells and isogeneic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations specific to A53T -syn mutant A9-DA neurons (hNs). We report a novel molecular pathway whereby basal as well as toxin-induced oxidative and nitrosative stress inhibits the MEF2C-PGC1 transcription network in A53T hNs compared to corrected controls, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small molecule high-throughput screening, we identify the MEF2C-PGC1 pathway as a new drug target for therapeutic benefit in PD. In the current study, isogenic hiPSCs differing exclusively at a single amino acid (A53T) were exposed to either 2.8uM paraquat in combination with 1uM maneb for 24h or PBS vehicle control. Gene expression profile was analysed to assess the effect of both the genotype and exposure regiment on gene expression.

2013-12-05 | E-GEOD-46798 | biostudies-arrayexpress

Expression data from monozygotic twins discordant for nicotine metabolism

Project description:The Nicotine Metabolic Ratio (NMR), the ratio of two stable metabolites of nicotine, cotinine and trans-3’hydroxycotinin, is a determinant of the number of cigarettes smoked per day (CPD), of smoking topography, responsiveness to treatment via transdermal nicotine for smoking cessation, and carcinogen activation and level. The predominant gene involved in nicotine metabolism is CYP2A6, a highly polymorphic locus located in a cluster of P450 cytochrome protein loci on chr19q13. A recent study comprehensively modeling CYP2A6 genetic variation at seven polymorphisms and a related Nicotine Metabolic Ratio, the cotinine: cotinine+nicotine ratio, explains 72% of NMRC/C+N variation. These results suggest that additional genes may be contributing to nicotine and cotinine metabolism directly or via interaction with CYP2A6 or other genes. To identify additional genes that may influence the NMR, we conducted a genome-wide gene expression analysis of lymphoblastoid cell line (LCL) gene expression in a sample of monozygotic twins discordant for the NMR.

2015-09-30 | GSE51284 | GEO

C. elegans embryos: control vs. mes-2 mutant

Project description:Transcriptional profiling of early C. elegans embryos comparing control (N2) embryos with mes-2 mutant embryos at different developmental stages: 2E (24-40 cells), 4E (50-90 cells) and 8E stage (100-200 cells). Goal was to determine the effects of mes-2 loss on global gene expression as embryos transit from a developmentally plastic state (2E stage) to the onset of differentiation (8E stage). Our microarray data showed that early-expressed genes remain active, differentiation genes fail to reach wild-type levels in mes-2 mutant embryos at the 8E stage.

2009-05-26 | GSE14913 | GEO

Relapse from nicotine abstinence increases the pacemaking frequency of cholinergic habenular neurons

Project description:The discovery of genetic variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula- interpeduncular axis as a critical relay circuit in the control of nicotine addiction Here we profile the cholinergic neurons of the medial habenula and identify the unique transcirptional features of this population of neurons.

2013-12-30 | GSE43164 | GEO

C. elegans embryos: control vs. mes-2 mutant

2010-05-18 | E-GEOD-14913 | biostudies-arrayexpress

Hedgehog Interaction Protein Acts in the Habenula to Regulate Nicotine Intake

Project description:Medial habenular (mHb) cholinergic neurons that project to the interpeduncular nucleus (IPn) regulate aversive behavioral responses to nicotine that protect against tobacco addiction. Little is known about the nicotine-evoked cellular or molecular adaptations in these neurons that influence the development of the smoking habit. Using in vivo calcium imaging and single-cell RNA sequencing, we show that a dose of nicotine that stimulates mHb neural activity evokes robust transcriptional plasticity in neuronal and non-neuronal cells in the mHb, including upregulated expression of Hedgehog-interacting protein (HHIP) in putative cholinergic neurons. Allelic variation in HHIP confers risk for smoking-related diseases including chronic obstructive pulmonary disease and lung cancer, but underlying mechanisms of action are unclear. Using Translating Ribosome Affinity Purification (TRAP) sequencing and RNAscope, we confirmed that Hhip transcripts are highly enriched in mHb cholinergic neurons. HHIP mutant mice exhibit hundreds of differentially expressed transcripts in the mHb and perturbed transcriptional responses to nicotine. Moreover, acute in vivo CRISPR/Cas9-mediated genomic cleavage of mHb Hhip attenuated noxious responses to nicotine and increased intravenous nicotine self-administration behavior in mice. In vitro knockdown of Hhip reduces intracellular calcium release to nicotine and increases Gli activity. These findings suggest that HHIP acts in the mHb to regulate nicotine intake and that HHIP alleles may increase vulnerability to smoking-related diseases by modulating mHb signaling and enhancing the addictive properties of tobacco.

2022-11-06 | GSE217000 | GEO

Temporal proteomic changes induced by nicotine in human cells: A quantitative proteomics approach

Project description:Nicotine is a prominent active compound in tobacco and many smoking cessation products. Some of the biological effects of nicotine are well documented in in vitro and in vivo systems; however, nominal data are available concerning the time-dependent changes on protein and phosphorylation events in response to nicotine. Here, we profiled the proteomes of SH-SY5Y and A549 cell lines subjected to acute (15min, 1h and 4h) or chronic (24h, 48h) nicotine exposures. We used sample multiplexing (TMTpro16) and quantified more than 9,000 proteins and over 7,000 phosphorylation events per cell line. Among our findings, we determined a decrease in mitochondrial protein abundance for SH-SY5Y, while we detected alterations in several immune pathways, such as the complement system, for A549. We also explored the proposed association between smoking and SARS-CoV2. Here, we found several host proteins known to interact with viral proteins that were affected by nicotine in a time dependent manner. This dataset can be mined further to investigate the potential role of nicotine in different biological contexts.

2021-05-11 | PXD023108 | Pride

In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain

Project description:Background; Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical grey matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco. Results: In this study we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed false discovery correction (FDR ² 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions of GNA15 and SDHAP3 of smoking-exposed fetuses. Furthermore, developmental up-regulation of SDHAP3 mRNA was delayed in smoking- exposed fetuses. DMRÕs passing FDR were found by interaction analysis between gestational age and smoking exposure annotated to SYCE3, C21orf56/LSS, SPAG1 and RNU12/POLDIP3. Utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We further showed that nicotine impedes the differentiation of neurons in vitro independent of cell death. Conclusions; We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine.

2017-02-19 | GSE90871 | GEO

An Immune and Inflammation Signature in Prostate Tumors of Smokers (part 3)

Project description:Current smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor induces metastasis. To identify smoking-induced alterations in human prostate tumors, we analyzed gene and protein expression of tumors from current, past, and never smokers and observed distinct molecular alterations in current smokers. Specifically, an immune and inflammation signature was identified in prostate tumors of current smokers that was either attenuated or absent in past and never smokers. Key characteristics of this signature included augmented immunoglobulin expression by tumor-infiltrating B cells, NF-kB activation, and increased interleukin-8 in tumor and blood. In an alternate approach to characterize smoking-induced oncogenic alterations, we explored the effects of nicotine in prostate cancer cells and prostate cancer-prone TRAMP mice. These experiments showed that nicotine increases both invasiveness of human prostate cancer cells and metastasis in tumor-bearing TRAMP mice, indicating that nicotine can induce a phenotype that resembles the epidemiology of smoking-associated prostate cancer progression. In summary, we describe distinct oncogenic alterations in prostate tumors from current smokers and show that nicotine can enhance prostate cancer metastasis. TRAMP mice in five replicates received either tap water or a solution of 250 µg/ml of nicotine [nicotine tartrate salt (Sigma-Aldrich, St. Louis, MO)] in tap water

2015-04-22 | E-GEOD-68137 | biostudies-arrayexpress

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