References of "Delcambre, Sylvie 50001597"
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See detailMtDNA deletions discriminate affected from unaffected LRRK2 mutation carriers
Ouzren, Nassima UL; Delcambre, Sylvie UL; Ghelfi, Jenny UL et al

in Annals of Neurology (2019), 86(2), 324-326

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See detailIntegration of VDR genome wide binding and GWAS genetic variation data reveals co-occurrence of VDR and NF-κB binding that is linked to immune phenotypes
Singh, Prashant K.; van den Berg, Patrick R.; Long, Mark D. et al

in BMC Genomics (2017)

Background The nuclear hormone receptor superfamily acts as a genomic sensor of diverse signals. Their actions are often intertwined with other transcription factors. Nuclear hormone receptors are targets ... [more ▼]

Background The nuclear hormone receptor superfamily acts as a genomic sensor of diverse signals. Their actions are often intertwined with other transcription factors. Nuclear hormone receptors are targets for many therapeutic drugs, and include the vitamin D receptor (VDR). VDR signaling is pleotropic, being implicated in calcaemic function, antibacterial actions, growth control, immunomodulation and anti-cancer actions. Specifically, we hypothesized that the biologically significant relationships between the VDR transcriptome and phenotype-associated biology could be discovered by integrating the known VDR transcription factor binding sites and all published trait- and disease-associated SNPs. By integrating VDR genome-wide binding data (ChIP-seq) with the National Human Genome Research Institute (NHGRI) GWAS catalog of SNPs we would see where and which target gene interactions and pathways are impacted by inherited genetic variation in VDR binding sites, indicating which of VDR’s multiple functions are most biologically significant. Results To examine how genetic variation impacts VDR function we overlapped 23,409 VDR genomic binding peaks from six VDR ChIP-seq datasets with 191,482 SNPs, derived from GWAS-significant SNPs (Lead SNPs) and their correlated variants (r 2 > 0.8) from HapMap3 and the 1000 genomes project. In total, 574 SNPs (71 Lead and 503 SNPs in linkage disequilibrium with Lead SNPs) were present at VDR binding loci and associated with 211 phenotypes. For each phenotype a hypergeometric test was used to determine if SNPs were enriched at VDR binding sites. Bonferroni correction for multiple testing across the 211 phenotypes yielded 42 SNPs that were either disease- or phenotype-associated with seven predominately immune related including self-reported allergy; esophageal cancer was the only cancer phenotype. Motif analyses revealed that only two of these 42 SNPs reside within a canonical VDR binding site (DR3 motif), and that 1/3 of the 42 SNPs significantly impacted binding and gene regulation by other transcription factors, including NF-κB. This suggests a plausible link for the potential cross-talk between VDR and NF-κB. Conclusions These analyses showed that VDR peaks are enriched for SNPs associated with immune phenotypes suggesting that VDR immunomodulatory functions are amongst its most important actions. The enrichment of genetic variation in non-DR3 motifs suggests a significant role for the VDR to bind in multimeric complexes containing other transcription factors that are the primary DNA binding component. Our work provides a framework for the combination of ChIP-seq and GWAS findings to provide insight into the underlying phenotype-associated biology of a given transcription factor. [less ▲]

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See detailIn vitro Metabolic Studies of Dopamine Synthesis and the Toxicity of L-DOPA in Human Cells
Delcambre, Sylvie UL

Doctoral thesis (2016)

This work is divided in two parts. In the first, I investigated the effects of 2,3- dihydroxy-L-phenylalanine (L-DOPA) on the metabolism of human tyrosine hydroxylase (TH)-positive neuronal LUHMES cells ... [more ▼]

This work is divided in two parts. In the first, I investigated the effects of 2,3- dihydroxy-L-phenylalanine (L-DOPA) on the metabolism of human tyrosine hydroxylase (TH)-positive neuronal LUHMES cells. L-DOPA is the gold standard treatment for Parkinson’s disease (PD) and its effects on cellular metabolism are controversial. It induced a re-routing of intracellular carbon supplies. While glutamine contribution to tricarboxylic acid (TCA) cycle intermediates increased, glucose contribution to the same metabolites decreased. Carbon contribution from glucose was decreased in lactate and was compensated by an increased pyruvate contribution. Pyruvate reacted with hydrogen peroxide generated during the auto-oxidation of L-DOPA and lead to an increase of acetate in the medium. In the presence of L-DOPA, this acetate was taken up by the cells. In combination with an increased glutamate secretion, all these results seem to point towards a mitochondrial complex II inhibition. In the second part of this work, I studied and compared dopamine (DA)-producing in vitro systems. First, I compared gene and protein expression of catecholamine (CA)- related genes. Then, I performed molecular engineering to increase TH expression in LUHMES and SH-SY5Y cells. This was sufficient to induce DA production in SH-SY5Y, but not in LUHMES cells, indicating that TH expression is not sufficient to characterize dopaminergic neurons. Therefore I used SH-SY5Y cells overexpressing TH to study substrates for DA production. Upon overexpression of aromatic amino acid decarboxylase (AADC), LUHMES cells produced DA after L-DOPA supplementation. This model was useful to study L-DOPA uptake in LUHMES cells and I showed that L-DOPA is imported via large amino acid transporter (LAT). In conclusion, the expression of TH is not sufficient to obtain a DA-producing cell system and this work opened many and answered some questions about DA metabolism. [less ▲]

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See detailStable Isotope-Assisted Evaluation of Different Extraction Solvents for Untargeted Metabolomics of Plants
Doppler, Maria; Kluger, Bernhard; Bueschl, Christoph et al

in International Journal of Molecular Sciences (2016)

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics ... [more ▼]

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics , which allows for the first time every detected feature to be considered for method evaluation. The efficiency and complementarity of commonly used extraction solvents, namely 1 + 3 (v/v) mixtures of water and selected organic solvents (methanol, acetonitrile or methanol/acetonitrile 1 + 1 (v/v)), with and without the addition of 0.1% (v/v) formic acid were compared. Four different wheat organs were sampled, extracted and analysed by LC-HRMS. Data evaluation was performed with the in-house-developed MetExtract II software and R. With all tested solvents a total of 871 metabolites were extracted in ear, 785 in stem, 733 in leaf and 517 in root samples, respectively. Between 48% (stem) and 57% (ear) of the metabolites detected in a particular organ were found with all extraction mixtures, and 127 of 996 metabolites were consistently shared between all extraction agent/organ combinations. In aqueous methanol, acidification with formic acid led to pronounced pH dependency regarding the precision of metabolite abundance and the number of detectable metabolites, whereas extracts of acetonitrile-containing mixtures were less affected. Moreover, methanol and acetonitrile have been found to be complementary with respect to extraction efficiency. Interestingly, the beneficial properties of both solvents can be combined by the use of a water-methanol-acetonitrile mixture for global metabolite extraction instead of aqueous methanol or aqueous acetonitrile alone. [less ▲]

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See detailDopamine Metabolism and Reactive Oxygen Species Production
Delcambre, Sylvie UL

in Buhlman, Lori (Ed.) Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease (2016)

Due to their chemical nature, dopamine and its metabolites are easily oxidized—a process often accompanied by the production of reactive oxygen species. While the MAO-mediated degradation of dopamine ... [more ▼]

Due to their chemical nature, dopamine and its metabolites are easily oxidized—a process often accompanied by the production of reactive oxygen species. While the MAO-mediated degradation of dopamine leads to the formation of hydrogen peroxide, the autoxidation of many intermediates of dopamine metabolism produces highly reactive quinones. These quinones can bind to cysteinyl residues of reduced GSH or proteins, leading to their inactivation if this residue is located in the active site of a protein. One way to overcome this problem is to increase production or uptake of antioxidants such as GSH or ascorbate. Interaction with astrocytes is an important fact for dopaminergic neuron survival: astrocytes provide the neurons with the GSH-precursor glutamine and are able to degrade excessive dopamine released by neurons. In dopaminergic neurons, excessive amounts of catecholamines can also be inactivated by their polymerization to neuromelanin. This polymer pigment itself can, however, have both a protective or deleterious effect, depending on the cellular context. It should be noted that although l-DOPA still represents the state-of-the-art treatment for Parkinson’s disease, it also represents a catecholamine that can contribute to oxidative stress in already damaged dopaminergic neurons. Oxidative damage outside the brain induced by longtime l-DOPA treatment (e.g., in melanocytes) has often been discussed; however, there is little clinical evidence for that theory. Finally, dopamine metabolism can be altered by genetic factors such as tyrosine hydroxylase deficiency or genetic variants of the dopamine transporter, as well as environmental factors such as pesticides or drugs. [less ▲]

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See detailLoss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism
Meiser, Johannes UL; Delcambre, Sylvie UL; Wegner, André UL et al

in Neurobiology of disease (2016), 89

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an ... [more ▼]

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches. [less ▲]

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