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Published on March 12, 2008

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The DISC1 Pathway in Schizophrenia, Learning, Memory and Mood:  Centre for Molecular Medicine Medical Genetics Section University of Edinburgh Molecular Medicine Centre Western General Hospital Campus EDINBURGH The DISC1 Pathway in Schizophrenia, Learning, Memory and Mood THANKS TO..:  THANKS TO.. Douglas Blackwood Walter Muir Kirsty Millar Shaun Mackie Ben Pickard Rachel James William Hennah Pippa Thomson Sheila Christie Sebby Cooper Fumiaki Ogawa Jennifer Chubb Nick Bradshaw Kathy Evans Pat Malloy COLLABORATORS at Merck Sharp & Dohme Nick Brandon, Miguel Camargo, Thomas Rosahl, Paul Whiting COLLABORATORS on PDE4B Miles Houslay, Elaine Huston, Elaine Hill, George Bailie, Hannah Murdoch, Glasgow COLLABORATORS on Disc1 Mouse Models Steve Clapcote & John Roder, Toronto, Canada Yoishi Gondo, RIKEN, Japan THE DISC1 CONSORTIUM Edinburgh (Hennah, Thomson, Blackwood, Muir & Porteous) Aberdeen (D St Clair), University College London (H Gurling), Helsinki (L Peltonen) SPONSORS Medical Research Council Wellcome Trust Merck Sharp & Dohme Organon Laboratories Chief Scientists Office of the Scottish Executive Health Department Cunningham Trust Stanley Medical Research Institute Scottish Hospitals Endowment Research Trust The Leading Causes of Disability Worldwide (Years of Life with Disability) Lopez & Murray, Nature Medicine, 4, 1241-1243 (1998) :  1. Unipolar depression 6. Bipolar Affective Disorder (manic depression) 9. Schizophrenia 10. Obsessive compulsive disorders One in a hundred will develop schizophrenia One in a hundred will develop bipolar disorder Both conditions are highly heritable 10 to 15 fold increased risk in first degree relatives Higher risk of bipolar if you have a relative with schizophrenia and vice versa 60-80% concordance in identical twins The Leading Causes of Disability Worldwide (Years of Life with Disability) Lopez & Murray, Nature Medicine, 4, 1241-1243 (1998) Slide4:  Schizophrenia positive symptoms of visual & auditory hallucinations, delusions, incoherent speech Bipolar Disorder (Manic Depression) manic phase: energetic, grandiose, elated, irritable, reduced sleep Slide5:  Bipolar Disorder (Manic Depression) despair, emptiness, inability to experience joy, lack of energy Schizophrenia negative symptoms of withdrawal & isolation, impaired attention & blunted emotions Psychiatric Genetics:  Psychiatric Genetics Clear evidence for major genetic component Familial clustering, but no simple patterns of inheritance Predictions: Genetic Heterogeneity Gene-Gene Interaction Gene-Environment Interaction Hypotheses: Common Disease, Common Variant (CDCV) Common Disease Rare Variant (CDRV) Methods: Family based linkage Population based association Candidate genes Cytogenetics Major psychosis co-segregating with a balanced t(1;11) translocation St Clair et al Lancet (1990), Blackwood et al AmJHumGenet (2001):  Major psychosis co-segregating with a balanced t(1;11) translocation St Clair et al Lancet (1990), Blackwood et al AmJHumGenet (2001) major psychiatric illness (SCZ, BPAD, RMD) minor psychiatric illness (ANX, ALC, MIND) unaffected t(1:11) The t(1;11) breakpoint & linkage to psychosis:  1 1q42 11q14 11 The t(1;11) breakpoint & linkage to psychosis 50-fold elevated risk LOD = 3.4 MLOD = 7.1 Dominant, variable penetrance, broad diagnosis CHROMOSOME 1 BREAKPOINT Millar et al, Hum. Mol. Gen, 2000:  CHROMOSOME 1 BREAKPOINT Millar et al, Hum. Mol. Gen, 2000 translocation breakpoint Novel, 13 exons, ~7.5kb mRNA, 854 amino acids, ~100kD protein Disrupted in Schizophrenia 1 DISC1 DISC1 Association Timeline:  DISC1 Association Timeline 1990 Translocation between chromosomes 1 and 11 associates with SCZ & major mental illness 2000 2006 DISC1 Identified at 1q42; Translocation association with SCZ, BPAD, Major depression SCZ-like P300 deficit in all t(1;11) carriers Schizoaffective disorder Bipolar disorder Major depression Working memory Attention Cognition Gray Matter Volume 2007 2002 2004 Schizophrenia Slide11:  SCHIZOPHRENIA SCHIZOAFFECTIVE DISORDER BIPOLAR AFFECTIVE DISORDER Linkage & Association between DISC1 & Psychiatric Disorder translocation BRITAIN & ICELAND TAIWAN FINLAND FINLAND NORTH-AMERICA SCOTLAND EUROPE MAJOR DEPRESSION JAPAN Leu607Phe Ser704Cys Hennah et al, Scz Bulletin, 2006 Hashimoto et al, HumMolGen, 2006 Multiple lines of supportive genetic evidence, but no convergence or validated functional variants Slide12:  Association between DISC1 & Cognition VISUAL WORKING MEMORY (SCHIZOPHRENIA) NORMAL COGNITIVE AGING SPATIAL WORKING MEMORY VERBAL LEARNING & MEMORY HIPPOCAMPAL STRUCTURE & FUNCTION GRAY MATTER VOLUME HIPPOCAMPAL VOLUME RAPID VISUAL SEARCH VERBAL WORKING MEMORY (SCHIZOPHRENIA) Leu607Phe Ser704Cys Biology of DISC1:  Biology of DISC1 Expression Interaction Biochemistry DISC1 Expression:  DISC1 Expression Widely expressed SCZ associated regions of the brain (hippocampus, dentate gyrus) peripheral blood lymphocytes / lymphoblastoid cell lines Developmentally regulated Highest during active neurogenesis Neonatal & adult Multiple isoforms Multiple cell compartments Nucleus Centrosome Cytoskeleton Cytoplasm Mitochondria 100 98 80 n-75 71 DISC1 Mutiple, Isoform-specific Subcellular Locations & Interactions:  DISC1 Mutiple, Isoform-specific Subcellular Locations & Interactions DISC1 Structure & Interacting Proteins:  REGIONS OF COILED-COIL FORMING POTENTIAL NUCLEAR LOCALISATION SIGNALS S/F-RICH MOTIF DISC1 Structure & Interacting Proteins Yeast 2 Hybrid Co-localisation Co-immunoprecipitation Functional interaction Slide17:  DISC1 interacts with proteins required for neurodevelopment & neuronal function NUDE / NUDEL: neuronal migration, corticogenesis & axonal outgrowth NUDEL: endo oligopeptidase that may regulate neuropeptide action in the CNS LIS1: lissencephaly 1 (‘smooth brain’), binds NUDE/NUDEL FEZ1: fasciculation and elongation zeta protein 1, neurite outgrowth, neuronal differentiation PDE4B: regulates compartmentalised cAMP signalling Effect of t(1;11) DISC1 mutation Millar et al., Science, 2005:  Effect of t(1;11) DISC1 mutation Millar et al., Science, 2005 Evidence for DISC1 haploinsufficiency Prediction: reduced interaction with all DISC1 interactors J. Kirsty Millar1, Benjamin S. Pickard1, Shaun Mackie1, Rachel James1, Sheila Christie1, Sebastienne R. Buchanan1, M. Pat Malloy1, Jennifer E. Chubb1, Elaine Huston2, George S. Baillie2, Elaine V. Hill2, Miles D. Houslay2, Nicholas J. Brandon3, Jean-Christophe Rain4, L. Miguel Camargo3, Paul J. Whiting3, Douglas H.R. Blackwood1,5, Walter J. Muir1,5, David J. Porteous1. Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK 2Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, UK 3Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK 43HYBRIGENICS S.A., 3-5 Impasse Reille–75014 Paris, France 5Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK:  DISC1 and PDE4 Are Interacting Genetic Factors in Schizophrenia that Regulate cAMP Signalling Science, 310, 1187-1191 (2005) J. Kirsty Millar1, Benjamin S. Pickard1, Shaun Mackie1, Rachel James1, Sheila Christie1, Sebastienne R. Buchanan1, M. Pat Malloy1, Jennifer E. Chubb1, Elaine Huston2, George S. Baillie2, Elaine V. Hill2, Miles D. Houslay2, Nicholas J. Brandon3, Jean-Christophe Rain4, L. Miguel Camargo3, Paul J. Whiting3, Douglas H.R. Blackwood1,5, Walter J. Muir1,5, David J. Porteous1. Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK 2Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, UK 3Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK 43HYBRIGENICS S.A., 3-5 Impasse Reille–75014 Paris, France 5Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK Genomics & Biology Converge & Corroborate PDE4B identified as a DISC1 interactor AND Psychosis associated t(1;16) disrupts PDE4B Millar et al Science 2005:  PDE4B identified as a DISC1 interactor AND Psychosis associated t(1;16) disrupts PDE4B Millar et al Science 2005 Proband with SCZ & cousin with psychosis Half normal levels of PDE4B Expression: Haploinsufficiency PDE4B Association in Schizophrenia Pickard et al, 2007 Phosphodiesterase 4B (PDE4B) is very interesting because:  Phosphodiesterase 4B (PDE4B) is very interesting because PDE’s are sole means of inactivating intracellular cAMP, a key second messenger in the brain. PDE4 is involved in learning, memory and mood in fly & mouse. PDE4 is target of antidepressant rolipram. Slide22:  The head domain of DISC1 binds the UCR2 domain of PDE4B Binding is dynamic, cAMP regulated, phosphorylation dependent and PKA mediated +cAMP -cAMP Slide23:  PDE4 A, B, C & D isoforms Unique N-termini Sub-cellular targeting cAMP compartmentalised signalling cAMP gradients Antidepressant rolipram sensitive Slide24:  N-terminal ‘globular’ head C-terminal helical tail B B All B All UCR2 Catalytic DISC1-PDE4 Interaction is Isoform Specific Murdoch et al, 2007 J Neuroscience, under revision ? ? All All 100kD 71kD ? DISC1 multiple functional motifs & interaction domains multiple targets for mutation & modulation mutation class specific effects:  DISC1 multiple functional motifs & interaction domains multiple targets for mutation & modulation mutation class specific effects Limitations of Human Studies of Brain Disorders:  Does modulation / mutation of Mouse Disc1 inform on the human conditions of SCZ & BPAD? Limitations of Human Studies of Brain Disorders Disc1 RNAi in utero inhibits neuronal migration in mouse brain Kamiya et al Nature Cell Biol 2005:  Disc1 RNAi in utero inhibits neuronal migration in mouse brain Kamiya et al Nature Cell Biol 2005 Reduced Migration, Polarity & Arborisation Slide28:  Behavioral Phenotypes of Disc1 Missense Mutations in Mice Clapcote et al, 2007 Neuron, 54, 387-402 ENU Missense Mutations in Disc1 Exon2:  ENU Missense Mutations in Disc1 Exon2 Reduced Brain Volume in Disc1 Mutant Mice:  The Neurodevelopmental Hypothesis in SCZ -6% in 31L -13% in 100P Cerebellum, thalamus, cortex, entorhinal cortex Reduced Brain Volume in Disc1 Mutant Mice Mouse Behavioural Tests:  Arguello & Gogos, Neuron, 2006 Mouse Behavioural Tests Pre-Pulse Inhibition (PPI) & Latent Inhibition (LI) Measures of attention, information processing and working memory:  Pre-Pulse Inhibition (PPI) & Latent Inhibition (LI) Measures of attention, information processing and working memory PPI: does a low level stimulus inhibit a startle response to a strong stimulus? LI: can irrelevant stimuli be disregarded and memory formation inhibited to prevent information overload? Both PPI and LI are low in SCZ. Both PPI and LI can be measured in the mouse. Pre-Pulse Inhibition is low in 31L and lower still in 100P Disc1 mutants :  Pre-Pulse Inhibition is low in 31L and lower still in 100P Disc1 mutants +/+ < 31L/+ < 31L/31L < 100P/+ < 100P/100P = 100P/31L Pharmacological Responses in PPI:  Pharmacological Responses in PPI 31L rescued by buproprion, but not rolipram 100P rescued by rolipram, but not buproprion 100P, but not 31L, rescued by clozapine (atypical) and haloperidol (dopamine D2 antagonist) Latent Inhibition is low in 31L and lower still in 100P Disc1 Mutants:  Latent Inhibition is low in 31L and lower still in 100P Disc1 Mutants The Antipsychotic Clozapine Rescues the Latent Inhibition Deficit in 100P Disc1 Mutants:  The Antipsychotic Clozapine Rescues the Latent Inhibition Deficit in 100P Disc1 Mutants Open Field Activity 100P Disc1 mutants are hyperactive:  Open Field Activity 100P Disc1 mutants are hyperactive 100P/100P >> 100P/+ = 31L/31L = 31L/+ = +/+ Choice Delay Test of Working Memory 100P Disc1 mutants are slower learners:  Choice Delay Test of Working Memory 100P Disc1 mutants are slower learners Forced Swim Test 31L Disc1 mutants show marked despair:  Forced Swim Test 31L Disc1 mutants show marked despair Despair is rescued by bupropion AND rolipram in wild type, but ONLY by bupropion in 31L/31L Summary of Behaviour & Drug Responses in 100P & 31L Disc1 Mutants:  Summary of Behaviour & Drug Responses in 100P & 31L Disc1 Mutants PPI & LI deficits indicate sensory motor gating & attention deficits 100P more severe than 31L PPI deficit in 100P partially alleviated by typical (haloperidol) & atypical (clozapine) antipsychotics LI deficit in 100P rescued by clozapine 31L homozygotes show depressive like behaviour in the forced swim test which is reversed by bupoprion, but not rolipram Learning, Memory & Mood cAMP Signalling & PDE4 :  Learning, Memory & Mood cAMP Signalling & PDE4 Reduced PDE4B activity in 31L, but not 100P Slide42:  N-terminal ‘globular’ head C-terminal helical tail B B All B All Q31L L100P L607F C704S UCR2 Catalytic DISC1 Missense Mutations & PDE4 Binding Domains DISC1 Interactors as Independent & Co-dependent Genetic Risk Factors:  DISC1 Interactors as Independent & Co-dependent Genetic Risk Factors FEZ1 Association (Yamada et al, 2004) PDE4B Cytogenetics (Millar et al, 2005) Association (Tomppo et al, 2006; Pickard et al, 2007) PDE4D Association (Tomppo et al, 2006) NUDEL (NDEL1) DISC1 ser704cys stratified association & functional brain imaging (Malhorta et al, 2006) NUDE (NDE1) DISC1 HEP3 stratified linkage & association (Hennah et al, 2007) DISC1 Genetic Heterogeneity & Genetic Interplay:  DISC1 Genetic Heterogeneity & Genetic Interplay Combined analysis of Aberdeen, Edinburgh, London & Helsinki cohorts Finnish SNP and London SNP associate with BPAD Stratification on Finnish or London SNP identifies a third SNP Combined SNPs increase risk of SCZ 1 SNP alone: BPAD >> SCZ 2 SNP’s together: SCZ > BPAD Conclusions:  Conclusions The genetic & biological evidence supports a generalised role for DISC1 in major mental illness & cognition DISC1 is a scaffold protein that assembles & regulates key neurodevelopmental & neurosignaling proteins Disc1 missense mutants model behavioural, pharmacological & brain structural features of schizophrenia & mood disorder The DISC1 pathway offers a route towards a mechanistic understanding of these poorly understood & debilitating disorders, prerequisite to development of rational interventions Schizophrenia & Bipolar Disorder:  Schizophrenia & Bipolar Disorder One in fifty will develop schizophrenia or bipolar disorder Current treatment is unsatisfactory Major unmet need Discovery of DISC1 pathway paves way to Molecular basis of disease Biomarker discovery Diagnosis, prognosis & treatment response Rational drug development

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