Christoph W Turck

Max Planck Institute of Psychiatry, München, Bavaria, Germany

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Publications (212)1170.78 Total impact

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    ABSTRACT: Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a and chronic administration of the mGluR5 inverse agonist CTEP on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated, and accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 KO mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, while overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.Neuropsychopharmacology accepted article preview online, 20 November 2014. doi:10.1038/npp.2014.308.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; · 8.68 Impact Factor
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    ABSTRACT: Abnormal structural/functional connectivity has been proposed to underlie the pathophysiology of schizophrenia. However, the biochemical basis of abnormal connectivity remains undefined.
    Schizophrenia Research 09/2014; · 4.59 Impact Factor
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    ABSTRACT: Although antidepressants have been used in the treatment of affective disorders for over 50 years, the precise mechanism of their action remains unknown. Treatment regimens are based by and large on empirical parameters and characterized by a trial and error scheme. A better understanding of the mechanisms involved in antidepressant drug response is of fundamental importance for the development of new compounds that have a higher success rate and specificity. In order to elucidate the molecular pathways involved in the action of antidepressants, we wish to identify brain areas, cell types and organelles that are targeted by antidepressant treatment in mice. Multi-isotope imaging mass spectrometry allows a quantitative approach to this analysis, enabling us to delineate antidepressant effect on protein synthesis in the brain at single cell and organelle resolution. In these experiments, we obtained a global analysis of protein turnover in the hippocampus dentate gyrus and in the Cornu Ammonis regions, together with a subcellular analysis in the granular cells and others. Copyright © 2014 John Wiley & Sons, Ltd.
    Surface and Interface Analysis 07/2014; · 1.39 Impact Factor
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    ABSTRACT: Here we report the downregulation of S100B in the nuclear proteome of the corpus callosum from nine schizophrenia patients compared to seven mentally healthy controls. Our data have been obtained primarily by mass spectrometry and later confirmed by Western blot. This is an intriguing finding coming from a brain region which is essentially composed by white matter, considering the potential role of S100B in the control of oligodendrocyte maturation. This data reinforce the importance of oligodendrocytes in schizophrenia, shedding more light to its pathobiology.
    European Archives of Psychiatry and Clinical Neuroscience 02/2014; · 3.36 Impact Factor
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    ABSTRACT: Major depressive disorder (MDD) is one of the leading causes of global disability. It is a risk factor for noncompliance with medical treatment, with about 40% of patients not responding to currently used antidepressant drugs. The identification and clinical implementation of biomarkers that can indicate the likelihood of treatment response are needed in order to predict which patients will benefit from an antidepressant drug. While analyzing the blood plasma proteome collected from MDD patients before the initiation of antidepressant medication, we observed different fibrinogen alpha (FGA) levels between drug responders and nonresponders. These results were replicated in a second set of patients. Our findings lend further support to a recently identified association between MDD and fibrinogen levels from a large-scale study.
    Translational psychiatry. 01/2014; 4:e352.
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    ABSTRACT: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has fast-acting antidepressant activities and is used for major depressive disorder (MDD) patients who show treatment resistance towards drugs of the selective serotonin reuptake inhibitor (SSRI) type. In order to better understand Ketamine's mode of action, a prerequisite for improved drug development efforts, a detailed understanding of the molecular events elicited by the drug is mandatory. In the present study we have carried out a time-dependent hippocampal metabolite profiling analysis of mice treated with Ketamine. After a single injection of Ketamine, our metabolomics data indicate time-dependent metabolite level alterations starting already after 2 h reflecting the fast antidepressant effect of the drug. In silico pathway analyses revealed that several hippocampal pathways including glycolysis/gluconeogenesis, pentose phosphate pathway and citrate cycle are affected, apparent by changes not only in metabolite levels but also connected metabolite level ratios. The results show that a single injection of Ketamine has an impact on the major energy metabolism pathways. Furthermore, seven of the identified metabolites qualify as biomarkers for the Ketamine drug response.
    Translational psychiatry. 01/2014; 4:e481.
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    ABSTRACT: No comprehensive metabolic profile of trait anxiety is to date available. To identify metabolic biosignatures for different anxiety states, we compared mice selectively inbred for ∼40 generations for high (HAB), normal (NAB) or low (LAB) anxiety-related behavior. Using a mass spectrometry-based targeted metabolomics approach, we quantified the levels of 257 unique metabolites in the cingulate cortex and plasma of HAB, NAB and LAB mice. We then pinpointed affected molecular systems in anxiety-related behavior by an in silico pathway and network prediction analysis followed by validation of in silico predicted alterations with molecular assays. We found distinct metabolic profiles for different trait anxiety states and detected metabolites with altered levels both in cingulate cortex and plasma. Metabolomics data revealed common candidate biomarkers in cingulate cortex and plasma for anxiety traits and in silico pathway analysis implicated amino acid metabolism, pyruvate metabolism, oxidative stress and apoptosis in the regulation of anxiety-related behavior. We report characteristic biosignatures for trait anxiety states and provide a network map of pathways involved in anxiety-related behavior. Pharmacological targeting of these pathways will enable a mechanism-based approach for identifying novel therapeutic targets for anxiety disorders.
    Journal of Psychiatric Research. 01/2014;
  • Biological psychiatry 01/2014; · 8.93 Impact Factor
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    ABSTRACT: Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.
    Frontiers in Cellular Neuroscience 01/2014; 8:384. · 4.47 Impact Factor
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    ABSTRACT: Defining the proteomes encoded by each chromosome and characterizing proteins related to human illnesses are among the goals of the Chromosome-Centric Human Proteome Project (C-HPP) and the Biology and Disease-driven HPP. Following these objectives, we investigated the proteomes of the human anterior temporal lobe (ATL) and corpus callosum (CC) collected postmortem from eight subjects. Using a label-free GeLC-MS/MS approach, we identified 2,454 proteins in the ATL and 1,887 in the CC through roughly 7,500 and 5,500 peptides respectively. Considering that the ATL is a gray matter region while the CC is a white matter, they presented proteomes specific to their functions. Besides, 38 proteins were found to be differentially expressed between the two regions. Furthermore, the proteome datasets were classified according to their chromosomal origin and five proteins were evidenced at MS level for the first time. We identified 70 proteins of the chromosome 15 - one of them for the first time by MS - which were submitted to an in silico pathway analysis. These revealed branch point proteins associated to Prader-Willi and Angelman syndromes and dyskeratosis congenital, which are chromosome 15 associated diseases. Data presented here can be a useful for brain disorders studies as well as for contributing to the C-HPP initiative. Our data are publicly available as resource data to C-HPP participant groups at http://yoda.iq.ufrj.br/Daniel/chpp2013. Additionally, the mass spectrometry proteomics data have been deposited to the ProteomeXchange with identifier PXD000547 for the corpus callosum and PXD000548 for the anterior temporal lobe.
    Journal of Proteome Research 11/2013; · 5.06 Impact Factor
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    ABSTRACT: Significant progress in elucidating the genetic etiology of anxiety and depression has been made during the last decade through a combination of human and animal studies. In this study, we aimed to discover genetic loci linked with anxiety as well as depression in order to reveal new candidate genes. Therefore, we initially tested the behavioral sensitivity of 543 F2 animals derived from an intercross of C57BL/6J and C3H/HeJ mice in paradigms for anxiety and depression. Next, all animals were genotyped with 269 microsatellite markers with a mean distance of 5.56 cM. Finally, a Quantitative Trait Loci (QTL) analysis was carried out, followed by selection of candidate genes. The QTL analysis revealed several new QTL on chromosome 5 with a common core interval of 19 Mb. We further narrowed this interval by comparative genomics to a region of 15 Mb. A database search and gene prioritization revealed Enoph1 as the most significant candidate gene on the prioritization list for anxiety and also for depression fulfilling our selection criteria. The Enoph1 gene, which is involved in polyamine biosynthesis, is differently expressed in parental strains, which have different brain spermidine levels and show distinct anxiety and depression-related phenotype. Our result suggests a significant role in polyamines in anxiety and depression-related behaviors. Enoph1, an enzyme of the methionine salvage pathway involved in polyamine biosynthesis, was identified by QTL analysis as a candidate gene contributing to stress-sensitivity in a F2 population of mice derived from C57BL/6J × C3H/HeJ intercrosses. The parental strains express two different protein variants of Enoph1, show different Enoph1 expression levels, and have different brain spermidine levels. These findings suggest that Enoph1 modulates stress sensitivity in these strains.
    Journal of Neurochemistry 11/2013; · 3.97 Impact Factor
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    ABSTRACT: Myelination of the central nervous system is performed by oligodendrocytes, which have been implicated in brain disorders such as multiple sclerosis and schizophrenia. We have used the human oligodendroglial cell line MO3.13 to establish an oligodendrocyte reference proteome database. Proteins were pre-fractionationated by SDS-PAGE and after in-gel digestion subjected to nano-flow liquid chromatography mass spectrometry (nLC-MS/MS) analysis. Approximately 11,600 unique peptides were identified and, after stringent filtering, resulted in 2,290 proteins representing 9 distinct biological processes and various molecular classes and functions. Oligodendrocyte-specific proteins such as MBP and CNP as well as proteins involved in multiple sclerosis and schizophrenia were also identified and are discussed. Proteins of this dataset have also been classified according to their chromosomal origin for providing useful data to the chromosome-centric human proteome project (C-HPP). Given the importance of oligodendrocytes in the etiology of demyelinating and oligodendrogial disorders, the MO3.13 proteome database will provide a valuable resource. The mass spectrometry proteomics data have been deposited to the ProteomeXchange with identifier PXD000263. This article is protected by copyright. All rights reserved.
    Proteomics 10/2013; · 4.43 Impact Factor
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    ABSTRACT: Psychiatric disorders are caused by perturbed molecular pathways that affect brain circuitries. The identification of specific biosignatures that are the result of altered pathway activities in major depression, bipolar disorder and schizophrenia can contribute to a better understanding of disease etiology and aid in the implementation of diagnostic assays. In the present study we identified disease-specific protein biosignatures in cerebrospinal fluid of depressed (n: 36), bipolar (n: 27) and schizophrenic (n: 35) patients using the Reverse Phase Protein Microarray technology. These biosignatures were able to stratify patient groups in an objective manner according to cerebrospinal fluid protein expression patterns. Correct classification rates were over 90%. At the same time several protein sets that play a role in neuronal growth, proliferation and differentiation (NEGR1, NPDC1), neurotransmission (SEZ6) and protection from oxidative damage (GPX3) were able to distinguish diseased from healthy individuals (n: 35) indicating a molecular signature overlap for the different psychiatric phenotypes. Our study is a first step toward implementing a psychiatric patient stratification system based on molecular biosignatures. Protein signatures may eventually be of use as specific and sensitive biomarkers in clinical trials not only for patient diagnostic and subgroup stratification but also to follow treatment response.
    Journal of Psychiatric Research 08/2013; · 4.09 Impact Factor
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    Biological psychiatry 05/2013; · 8.93 Impact Factor
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    ABSTRACT: Schizophrenia is a heterogeneous psychiatric disorder characterized by an array of clinical manifestations. Although the best known manifestations include serious effects on mood and behavior, patients can also display co-morbidities, including immune system or metabolic abnormalities. Thorough characterization of these conditions using proteomic profiling methods has increased our knowledge of these molecular differences and has helped to unravel the complexity and heterogeneity of this debilitating condition. This could lead to patient stratification through characterization of biochemically different subtypes of the disease. In addition, proteomic methods have recently been used for molecular characterization of the mechanism of action of antipsychotic medications in both preclinical models and patients. This has resulted in identification of molecular panels that show some promise for prediction of response or for monitoring treatment outcome. This review describes how proteomic profiling methods can impact the future of schizophrenia diagnosis and therapeutics, and facilitate personalized medicine approaches for more effective treatment management of schizophrenia patients.
    Genome Medicine 03/2013; 5(3):25. · 4.94 Impact Factor
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    ABSTRACT: CRH is a key regulator of neuroendocrine, autonomic, and behavioral response to stress. CRH-stimulated CRH receptor 1 (CRHR1) activates ERK1/2 depending on intracellular context. In a previous work, we demonstrated that CRH activates ERK1/2 in limbic areas of the mouse brain (hippocampus and basolateral amygdala). ERK1/2 is an essential mediator of hippocampal physiological processes including emotional behavior, synaptic plasticity, learning, and memory. To elucidate the molecular mechanisms by which CRH activates ERK1/2 in hippocampal neurons, we used the mouse hippocampal cell line HT22. We document for the first time that ERK1/2 activation in response to CRH is biphasic, involving a first cAMP- and B-Raf-dependent early phase and a second phase that critically depends on CRHR1 internalization and β-arrestin2. By means of mass-spectrometry-based screening, we identified B-Raf-associated proteins that coimmunoprecipitate with endogenous B-Raf after CRHR1 activation. Using molecular and pharmacological tools, the functional impact of selected B-Raf partners in CRH-dependent ERK1/2 activation was dissected. These results indicate that 14-3-3 proteins, protein kinase A, and Rap1, are essential for early CRH-induced ERK1/2 activation, whereas dynamin and vimentin are required for the CRHR1 internalization-dependent phase. Both phases of ERK1/2 activation depend on calcium influx and are affected by calcium/calmodulin-dependent protein kinase II inactivation. Thus, this report describes the dynamics and biphasic nature of ERK1/2 activation downstream neuronal CRHR1 and identifies several new critical components of the CRHR1 signaling machinery that selectively controls the early and late phases of ERK1/2 activation, thus providing new potential therapeutic targets for stress-related disorders.
    Molecular Endocrinology 01/2013; · 4.75 Impact Factor
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    ABSTRACT: Many quantitative proteomics methods rely on protein and peptide labeling with stable isotopes. We have recently found that the introduction of (15)N into organisms via in vivo metabolic labeling affects protein expression levels as well as metabolic pathways and behavioral phenotypes. Here, we present further evidence for a stable isotope effect based on the plasma proteome analysis of (15)N-labeled mice. We compared plasma proteomes of (15)N-labeled and unlabeled ((14)N) mice by quantitative MS. We found a number of protein level differences, some of which were verified immunochemically. In addition, we observed divergent chromatographic retention time and peak full width at half maximum (FWHM) between (15)N-labeled and (14)N tryptic peptides. Our data point towards a systemic effect of the introduction of heavy isotopes in vivo.
    Journal of proteomics 12/2012; · 5.07 Impact Factor
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    ABSTRACT: Peripheral blood mononuclear cells are accessible through blood collection and represent a useful source for investigations on disease mechanisms and treatment response. Aiming to build a reference proteome database we generated three proteome datasets from mononuclear cells (MNCs) using a combination of SDS-PAGE and nano flow liquid chromatography mass spectrometry (nLC-MS/MS). Experiments were performed in triplicates and 514 unique proteins were identified by at least 2 peptides with 95% confidence for all replicates. Identified proteins are associated with a range of dermatologic, inflammatory and neurological conditions as well as molecular processes such as free radical scavenging and cellular growth and proliferation. Mapping the MNC proteome provides a valuable resource for studies on disease pathogenesis and the identification of therapeutic targets.
    Proteomics 12/2012; · 4.43 Impact Factor
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    ABSTRACT: Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of monoamine reuptake inhibition are poorly understood and yet presumably important for the drugs' mode of action. In the present study we aimed at identifying hippocampal cellular pathway alterations in DBA/2 mice using paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Furthermore we identified biomarker candidates for the assessment of antidepressant treatment effects in plasma. Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo(15)N metabolic labeling combined with mass spectrometry. We also studied the time course of metabolite level changes in hippocampus and plasma using a targeted polar metabolomics profiling platform. In silico pathway analyses revealed profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. In the course of our analyses we also identified myo-inositol as a biomarker candidate for the assessment of antidepressant treatment effects in the periphery. This study defines the cellular response to paroxetine treatment at the proteome and metabolome levels in the hippocampus of DBA/2 mice and suggests novel SSRI modes of action that warrant consideration in antidepressant development efforts.
    Journal of Psychiatric Research 11/2012; · 4.09 Impact Factor
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    ABSTRACT: Several techniques based on stable isotope labeling are used for quantitative MS. These include stable isotope metabolic labeling methods for cells in culture as well as live organisms with the assumption that the stable isotope has no effect on the proteome. Here, we investigate the (15) N isotope effect on Escherichia coli cultures that were grown in either unlabeled ((14) N) or (15) N-labeled media by LC-ESI-MS/MS-based relative protein quantification. Consistent protein expression level differences and altered growth rates were observed between (14) N and (15) N-labeled cultures. Furthermore, targeted metabolite analyses revealed altered metabolite levels between (14) N and (15) N-labeled bacteria. Our data demonstrate for the first time that the introduction of the (15) N isotope affects protein and metabolite levels in E. coli and underline the importance of implementing controls for unbiased protein quantification using stable isotope labeling techniques.
    Proteomics 08/2012; · 4.43 Impact Factor

Publication Stats

8k Citations
1,170.78 Total Impact Points

Institutions

  • 2005–2014
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
  • 2013
    • Kanazawa University
      Kanazawa, Ishikawa, Japan
  • 2012–2013
    • Ludwig-Maximilians-University of Munich
      • Graduate School of Systemic Neurosciences
      München, Bavaria, Germany
  • 2011
    • Klinikum München-Ost
      München, Bavaria, Germany
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2009–2011
    • University of Bonn
      • Institute of Molecular Psychiatry
      Bonn, North Rhine-Westphalia, Germany
    • Max Planck Society
      München, Bavaria, Germany
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • CEP America
      Emeryville, California, United States
  • 2008–2009
    • University of São Paulo
      • Instituto de Psiquiatria (iPq)
      Ribeirão Preto, Estado de Sao Paulo, Brazil
  • 1987–2004
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Cellular and Molecular Pharmacology
      • • Cardiovascular Research Institute
      San Francisco, CA, United States
  • 2003
    • Genentech
      San Francisco, California, United States
  • 1987–2002
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1997–2000
    • University of California, Los Angeles
      • • Department of Microbiology, Immunology & Molecular Genetics
      • • Molecular Biology Institute
      Los Angeles, CA, United States
  • 1999
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1998
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States