Klaus-Armin Nave

Publications of Klaus-Armin Nave

• Fibroblast growth factor receptor signaling in oligodendrocytes regulates myelin sheath thickness.

  Authors: Miki Furusho, Jeffrey L Dupree, Klaus-Armin Nave, Rashmi Bansal

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 05/2012; 32(19):6631-41.

  Formation of the CNS white matter is developmentally tightly regulated, but the molecules and mechanisms of myelination control in the postnatal CNS are poorly understood. Here, we show that myelinFormation of the CNS white matter is developmentally tightly regulated, but the molecules and mechanisms of myelination control in the postnatal CNS are poorly understood. Here, we show that myelin growth is controlled by fibroblast growth factor (FGF) signaling, originally identified as a proliferative signal for oligodendrocyte precursor cells (OPCs) in vitro. We created two lines of mice lacking both FGF receptor 1 (Fgfr1) and Fgfr2 in oligodendrocyte-lineage cells but found that in these mice OPC proliferation and differentiation were unaffected. In addition, axonal ensheathment and the initiation of myelination were on time. However, the rapid growth of CNS myelin, normally occurring in the second postnatal week, was strongly inhibited. Throughout adulthood, the myelin sheath remained disproportionately thin relative to the axon caliber. In adult mice, mutant oligodendrocytes were normal in number, whereas the transcription of major myelin genes was reduced. This FGF receptor-mediated stimulation of mature oligodendrocytes could also be modeled in vitro, demonstrating that enhanced expansion of oligodendroglial processes requires signaling by extracellular signal regulated kinase-1 and -2 (Erk1/2), downstream mediators of mitogen-activated protein kinase (MAPK). In vivo, Erk1/2-MAPK activity was reduced in the hypomyelinated CNS of Fgfr1/Fgfr2 mutant mice. These studies reveal a previously unrecognized function of FGF receptor signaling in oligodendrocytes that contributes to the regulation of myelin sheath thickness and that uncouples the initiation of ensheathment from the later phase of continued myelin growth.

• Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy.

  Authors: Sandra Goebbels, Jan H Oltrogge, Susanne Wolfer, Georg L Wieser, Tobias Nientiedt, Alexander Pieper, Torben Ruhwedel, Matthias Groszer, Michael W Sereda, Klaus-Armin Nave

  EMBO molecular medicine. 04/2012;

  'Tomacula' and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the'Tomacula' and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P(3) at paranodal loops and Schmidt-Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.

• A myelin gene causative of a catatonia-depression syndrome upon aging.

  Authors: Nora Hagemeyer, Sandra Goebbels, Sergi Papiol, Anne Kästner, Sabine Hofer, Martin Begemann, Ulrike C Gerwig, Susann Boretius, Georg L Wieser, Anja Ronnenberg, Artem Gurvich, Stephan H Heckers, Jens Frahm, Klaus-Armin Nave, Hannelore Ehrenreich

  EMBO molecular medicine. 04/2012;

  Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2',3'-cyclicSevere mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase) is among the oligodendrocyte/myelin-associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional 'pro-inflammatory hit'. This phenotype is strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species with their partial CNP 'loss-of-function' genotype are best described as 'catatonia-depression' syndrome. As a consequence of perturbed CNP expression, mice show secondary low-grade inflammation/neurodegeneration. Analogously, in man, diffusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases.

• Quantitative and integrative proteome analysis of peripheral nerve myelin identifies novel myelin proteins and candidate neuropathy loci.

  Authors: Julia Patzig, Olaf Jahn, Stefan Tenzer, Sven P Wichert, Patricia de Monasterio-Schrader, Susanne Rosfa, Jörg Kuharev, Kuo Yan, Ingo Bormuth, Juliane Bremer, Adriano Aguzzi, Foteini Orfaniotou, Dörte Hesse, Markus H Schwab, Wiebke Möbius, Klaus-Armin Nave, Hauke Bernhard Werner

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 11/2011; 31(45):16369-86.

  Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorlyPeripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our compendium with the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the biogenesis, cell biology, metabolism, and pathology of myelin.

• Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.

  Authors: Viktorija Velanac, Tilmann Unterbarnscheidt, Wilko Hinrichs, Maike N Gummert, Tobias M Fischer, Moritz J Rossner, Amelia Trimarco, Veronica Brivio, Carla Taveggia, Michael Willem, Christian Haass, Wiebke Möbius, Klaus-Armin Nave, Markus H Schwab

  Glia. 11/2011; 60(2):203-17.

  Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that theMyelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.

• Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease.

  Authors: Ajit Singh Dhaunchak, David R Colman, Klaus-Armin Nave

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 10/2011; 31(42):14961-71.

  A large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded proteinA large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus-Merzbacher disease, a leukodystrophy defined by mutations of the PLP1 gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of several PLP1 point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.

• Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1.

  Authors: Damian Refojo, Martin Schweizer, Claudia Kuehne, Stefanie Ehrenberg, Christoph Thoeringer, Annette M Vogl, Nina Dedic, Marion Schumacher, Gregor von Wolff, Charilaos Avrabos, Chadi Touma, David Engblom, Günther Schütz, Klaus-Armin Nave, Matthias Eder, Carsten T Wotjak, Inge Sillaber, Florian Holsboer, Wolfgang Wurst, Jan M Deussing

  Science (New York, N.Y.). 09/2011; 333(6051):1903-7.

  The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, weThe corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and γ-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.

• In Vivo Imaging and Noninvasive Ablation of Pyramidal Neurons in Adult NEX-CreERT2 Mice.

  Authors: Amit Agarwal, Payam Dibaj, Celia M Kassmann, Sandra Goebbels, Klaus-Armin Nave, Markus H Schwab

  Cerebral cortex (New York, N.Y. : 1991). 08/2011;

  To study the function of individual neurons that are embedded in a complex neural network is difficult in mice. Conditional mutagenesis permits the spatiotemporal control of gene expression includingTo study the function of individual neurons that are embedded in a complex neural network is difficult in mice. Conditional mutagenesis permits the spatiotemporal control of gene expression including the ablation of cells by toxins. To direct expression of a tamoxifen-inducible variant of Cre recombinase (CreERT2) selectively to cortical neurons, we replaced the coding region of the murine Nex1 gene by CreERT2 cDNA via homologous recombination in embryonic stem cells. When injected with tamoxifen, adult NEX-CreERT2 mice induced reporter gene expression exclusively in projection neurons of the neocortex and hippocampus. By titrating the tamoxifen dosage, we achieved recombination in single cells, which allowed multiphoton imaging of neocortical neurons in live mice. When hippocampal projection neurons were genetically ablated by induced expression of diphteria toxin, within 20 days the inflammatory response included the infiltration of CD3+ T cells. This marks a striking difference from similar studies, in which dying oligodendrocytes failed to recruit cells of the adaptive immune system.

• A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity.

  Authors: Celia M Kassmann, Susanne Quintes, Jens Rietdorf, Wiebke Möbius, Michael Werner Sereda, Tobias Nientiedt, Gesine Saher, Myriam Baes, Klaus-Armin Nave

  FEBS letters. 05/2011; 585(14):2205-11.

  Demyelinating diseases of the nervous system cause axon loss but the underlying mechanisms are not well understood. Here we show by confocal and electron microscopy that in myelin-forming gliaDemyelinating diseases of the nervous system cause axon loss but the underlying mechanisms are not well understood. Here we show by confocal and electron microscopy that in myelin-forming glia peroxisomes are associated with myelin membranes. When peroxisome biogenesis is experimentally perturbed in Pex5 conditional mouse mutants, myelination by Schwann cells appears initially normal. However, in nerves of older mice paranodal loops become physically unstable and develop swellings filled with vesicles and electron-dense material. This novel model of a demyelinating neuropathy demonstrates that peroxisomes serve an important function in the peripheral myelin compartment, required for long-term axonal integrity.

• Transport of the major myelin proteolipid protein is directed by VAMP3 and VAMP7.

  Authors: Anke Feldmann, Jesa Amphornrat, Madeleine Schönherr, Christine Winterstein, Wiebke Möbius, Torben Ruhwedel, Lydia Danglot, Klaus-Armin Nave, Thierry Galli, Dieter Bruns, Jacqueline Trotter, Eva-Maria Krämer-Albers

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 04/2011; 31(15):5659-72.

  CNS myelination by oligodendrocytes requires directed transport of myelin membrane components and a timely and spatially controlled membrane expansion. In this study, we show the functionalCNS myelination by oligodendrocytes requires directed transport of myelin membrane components and a timely and spatially controlled membrane expansion. In this study, we show the functional involvement of the R-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE) proteins VAMP3/cellubrevin and VAMP7/TI-VAMP in myelin membrane trafficking. VAMP3 and VAMP7 colocalize with the major myelin proteolipid protein (PLP) in recycling endosomes and late endosomes/lysosomes, respectively. Interference with VAMP3 or VAMP7 function using small interfering RNA-mediated silencing and exogenous expression of dominant-negative proteins diminished transport of PLP to the oligodendroglial cell surface. In addition, the association of PLP with myelin-like membranes produced by oligodendrocytes cocultured with cortical neurons was reduced. We furthermore identified Syntaxin-4 and Syntaxin-3 as prime acceptor Q-SNAREs of VAMP3 and VAMP7, respectively. Analysis of VAMP3-deficient mice revealed no myelination defects. Interestingly, AP-3δ-deficient mocha mice, which suffer from impaired secretion of lysosome-related organelles and missorting of VAMP7, exhibit a mild dysmyelination characterized by reduced levels of select myelin proteins, including PLP. We conclude that PLP reaches the cell surface via at least two trafficking pathways with distinct regulations: (1) VAMP3 mediates fusion of recycling endosome-derived vesicles with the oligodendroglial plasma membrane in the course of the secretory pathway; (2) VAMP7 controls exocytosis of PLP from late endosomal/lysosomal organelles as part of a transcytosis pathway. Our in vivo data suggest that exocytosis of lysosome-related organelles controlled by VAMP7 contributes to myelin biogenesis by delivering cargo to the myelin membrane.

• A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.

  Authors: Sabrina Grube, Martin F Gerchen, Bartosz Adamcio, Luis A Pardo, Sabine Martin, Dörthe Malzahn, Sergi Papiol, Martin Begemann, Katja Ribbe, Heidi Friedrichs, Konstantin A Radyushkin, Michael Müller, Fritz Benseler, Joachim Riggert, Peter Falkai, Heike Bickeböller, Klaus-Armin Nave, Nils Brose, Walter Stühmer, Hannelore Ehrenreich

  EMBO molecular medicine. 03/2011; 3(6):309-19.

  KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing thatKCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for Schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype-based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells. In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans. To conclude, KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment.

• Cholesterol: a novel regulatory role in myelin formation.

  Authors: Gesine Saher, Susanne Quintes, Klaus-Armin Nave

  The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 02/2011; 17(1):79-93.

  Myelin consists of tightly compacted membranes that form an insulating sheath around axons. The function of myelin for rapid saltatory nerve conduction is dependent on its unique composition, highlyMyelin consists of tightly compacted membranes that form an insulating sheath around axons. The function of myelin for rapid saltatory nerve conduction is dependent on its unique composition, highly enriched in glycosphingolipids and cholesterol. Cholesterol emerged as the only integral myelin component that is essential and rate limiting for the development of CNS and PNS myelin. Experiments with conditional mouse mutants that lack cholesterol biosynthesis in oligodendrocytes revealed that only minimal changes of the CNS myelin lipid composition are tolerated. In Schwann cells of the PNS, protein trafficking and myelin compaction depend on cholesterol. In this review, the authors summarize the role of cholesterol in myelin biogenesis and myelin disease.

• A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia.

  Authors: Sergi Papiol, Martin Begemann, Albert Rosenberger, Heidi Friedrichs, Katja Ribbe, Sabrina Grube, Markus H Schwab, Henriette Jahn, Stefan Gunkel, Fritz Benseler, Klaus-Armin Nave, Hannelore Ehrenreich

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 01/2011; 156B(3):340-5.

  By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in theBy pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since Nrg1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Göttingen Research Association for Schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia.

• Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice.

  Authors: Derya Sargin, Ahmed El-Kordi, Amit Agarwal, Michael Müller, Sonja M Wojcik, Imam Hassouna, Swetlana Sperling, Klaus-Armin Nave, Hannelore Ehrenreich

  BMC biology. 01/2011; 9:27.

  Erythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shownErythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shown neuroprotective effects and improved cognition in patients with neuropsychiatric diseases treated with EPO. However, the critical EPO targets in brain are unknown, and separation of direct and indirect effects has remained difficult, given the role of EPO in hematopoiesis and brain oxygen supply. Here we demonstrate that mice with transgenic expression of a constitutively active EPOR isoform (cEPOR) in pyramidal neurons of cortex and hippocampus exhibit enhancement of spatial learning, cognitive flexibility, social memory, and attentional capacities, accompanied by increased impulsivity. Superior cognitive performance is associated with augmented long-term potentiation of cEPOR expressing neurons in hippocampal slices. Active EPOR stimulates neuronal plasticity independent of any hematopoietic effects and in addition to its neuroprotective actions. This property of EPOR signaling should be exploited for defining novel strategies to therapeutically enhance cognitive performance in disease conditions.

• The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients.

  Authors: Katja Ribbe, Heidi Friedrichs, Martin Begemann, Sabrina Grube, Sergi Papiol, Anne Kästner, Martin F Gerchen, Verena Ackermann, Asieh Tarami, Annika Treitz [......] Udo Schneider, Hans-Joachim Schwarz, Birgit Kröner-Herwig, Ursula Havemann-Reinecke, Jens Frahm, Walter Stühmer, Peter Falkai, Nils Brose, Klaus-Armin Nave, Hannelore Ehrenreich

  BMC psychiatry. 11/2010; 10:91.

  Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuableSchizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia. For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected. The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail. The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.

• PLP/DM20 expression and turnover in a transgenic mouse model of Pelizaeus-Merzbacher disease.

  Authors: Saadia A Karim, Jennifer A Barrie, Mailis C McCulloch, Paul Montague, Julia M Edgar, Debrah L Iden, Thomas J Anderson, Klaus-Armin Nave, Ian R Griffiths, Mark McLaughlin

  Glia. 11/2010; 58(14):1727-38.

  The most common cause of Pelizaeus-Merzbacher (PMD) is due to duplication of the PLP1 gene but it is unclear how increased gene dosage affects PLP turnover and causes dysmyelination. We have studiedThe most common cause of Pelizaeus-Merzbacher (PMD) is due to duplication of the PLP1 gene but it is unclear how increased gene dosage affects PLP turnover and causes dysmyelination. We have studied the dynamics of PLP/DM20 in a transgenic mouse model of PMD with increased gene dosage of the proteolipid protein gene (Plp1). The turnover of PLP/DM20 were investigated using an ex-vivo brain slice system and cultured oligodendrocytes. Homozygous mice have reduced PLP translation, markedly enhanced PLP degradation, and markedly reduced incorporation of PLP into myelin. Proteasome inhibition (MG132) prevented the enhanced degradation. Numerous autophagic vesicles are present in homozygous transgenic mice that may influence protein dynamics. Surprisingly, promoting autophagy with rapamycin decreases the degradation of nascent PLP suggesting autophagic vacuoles serve as a cellular storage compartment. We suggest that there are multiple subcellular fates of PLP/DM20 when overexpressed: the vast majority being degraded by the proteasome, a proportion sequestered into autophagic vacuoles, probably fused with endolysosomes, and only a small proportion entering the myelin sheath, where its association with lipid rafts is perturbed. Transgenic oligodendrocytes have fewer membrane sheets and this phenotype is improved with siRNA-mediated knockdown of PLP expression that promotes the formation of MBP+ myelin-like sheets. This finding suggests that RNAi technology is in principle applicable to improve CNS myelination when compromised by PLP/DM20 overexpression.

• Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes.

  Authors: Astrid Bottelbergs, Simon Verheijden, Leen Hulshagen, David H Gutmann, Sandra Goebbels, Klaus-Armin Nave, Celia Kassmann, Myriam Baes

  Glia. 10/2010; 58(13):1532-43.

  Ablation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied byAblation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied by demyelination, axonal degeneration, and gliosis. An oligodendrocyte selective Cnp-Pex5 knockout mouse model shows a similar pathology, but with later onset and slower progression. Until now, the link between these neurological anomalies and the known metabolic alterations, namely the accumulation of very long-chain fatty acids (VLCFA) and reduction of plasmalogens, has not been established. We now focused on the role of peroxisomes in neurons and astrocytes. A neuron-specific peroxisome knockout model, NEX-Pex5, showed neither microscopic nor metabolic abnormalities indicating that the lack of functional peroxisomes within neurons does not cause axonal damage. Axonal integrity and normal behavior was also preserved when peroxisomes were deleted from astrocytes in GFAP-Pex5(-/-) mice. Nevertheless, peroxisomal metabolites were dysregulated in brain including a marked accumulation of VLCFA and a slight reduction in plasmalogens. Interestingly, despite minor targeting of oligodendrocytes in GFAP-Pex5(-/-) mice, these metabolic perturbations were also present in isolated myelin indicating that peroxisomal metabolites are shuttled between different brain cell types. We conclude that absence of peroxisomal metabolism in neurons and astrocytes does not provoke the neurodegenerative phenotype observed after deleting peroxisomes from oligodendrocytes. Lack of peroxisomal metabolism in astrocytes causes increased VLCFA levels in myelin, but this has no major impact on neurological functioning.

• Structure and composition of myelinated axons: a multimodal synchrotron spectro-microscopy study.

  Authors: Tanja Ducić, Susanne Quintes, Klaus-Armin Nave, Jean Susini, Margaret Rak, Rémi Tucoulou, Mihai Alevra, Peter Guttmann, Tim Salditt

  Journal of structural biology. 10/2010; 173(2):202-12.

  We report elemental mappings on the sub-cellular level of myelinated sciatic neurons isolated from wild type mice, with high spatial resolution. The distribution of P, S, Cl, Na, K, Fe, Mn, Cu wasWe report elemental mappings on the sub-cellular level of myelinated sciatic neurons isolated from wild type mice, with high spatial resolution. The distribution of P, S, Cl, Na, K, Fe, Mn, Cu was imaged in freeze-dried as well as cryo-preserved specimen, using the recently developed cryogenic sample environment at beamline ID21 at the European Synchrotron Radiation Facility (ESRF). In addition, synchrotron radiation based Fourier transform infrared (FTIR) spectromicroscopy was used as a chemically sensitive imaging method. Finally single fiber diffraction in highly focused hard X-ray beams, and soft X-ray microscopy and tomography in absorption contrast are demonstrated as novel techniques for the study of single nerve fibers.

• Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.

  Authors: Martin Begemann, Sabrina Grube, Sergi Papiol, Dörthe Malzahn, Henning Krampe, Katja Ribbe, Heidi Friedrichs, Konstantin A Radyushkin, Ahmed El-Kordi, Fritz Benseler [......] Maren Stödtke, Christoph Szuszies, Kerstin Reim, Joachim Riggert, Fritz Eckstein, Peter Falkai, Heike Bickeböller, Klaus-Armin Nave, Nils Brose, Hannelore Ehrenreich

  Archives of general psychiatry. 09/2010; 67(9):879-88.

  Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variantsSchizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected] Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.

• Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination.

  Authors: Sandra Goebbels, Jan H Oltrogge, Robert Kemper, Ingo Heilmann, Ingo Bormuth, Susanne Wolfer, Sven P Wichert, Wiebke Möbius, Xin Liu, Corinna Lappe-Siefke, Moritz J Rossner, Matthias Groszer, Ueli Suter, Jens Frahm, Susann Boretius, Klaus-Armin Nave

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 06/2010; 30(26):8953-64.

  In the developing nervous system, constitutive activation of the AKT/mTOR (mammalian target of rapamycin) pathway in myelinating glial cells is associated with hypermyelination of the brain, but isIn the developing nervous system, constitutive activation of the AKT/mTOR (mammalian target of rapamycin) pathway in myelinating glial cells is associated with hypermyelination of the brain, but is reportedly insufficient to drive myelination by Schwann cells. We have hypothesized that it requires additional mechanisms downstream of NRG1/ErbB signaling to trigger myelination in the peripheral nervous system. Here, we demonstrate that elevated levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) have developmental effects on both oligodendrocytes and Schwann cells. By generating conditional mouse mutants, we found that Pten-deficient Schwann cells are enhanced in number and can sort and myelinate axons with calibers well below 1 microm. Unexpectedly, mutant glial cells also spirally enwrap C-fiber axons within Remak bundles and even collagen fibrils, which lack any membrane surface. Importantly, PIP3-dependent hypermyelination of central axons, which is observed when targeting Pten in oligodendrocytes, can also be induced after tamoxifen-mediated Cre recombination in adult mice. We conclude that it requires distinct PIP3 effector mechanisms to trigger axonal wrapping. That myelin synthesis is not restricted to early development but can occur later in life is relevant to developmental disorders and myelin disease.