Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We propose a five-phase model for schizophrenia: (A) Imperfect diet-induced fatty acid combinations are mobilized from reservoirs during stress exposure into the bloodstream; (B) Increased brain-blood barrier permeability, with a further penetration of fat into the brain matter; (C) Rearrangement in the regional neuronal membrane fatty acids with a further physical compression of the adjacent membrane protein structures causing conformational alterations; (D) Cytokines generate further physical changes, impairing single- or multi-dispersed ion channels placed on the same neuron; (E) Ion channels are blocked, with a subsequent biophysical ion shunt-to-ion flow propagation, which results in neuronal misfiring and the appearance of schizophrenic signs and symptoms.
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PMID:Biophysical shunt theory for neuropsychopathology: pentaphasic lipid-induced model for schizophrenia. 1036 75

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.
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PMID:Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. 1293 Dec 7

Linkage studies in families with schizophrenia have pointed to chromosome 22q12-q13 as one of several regions of the genome that may contain a susceptibility gene. The gene coding for synapsin III, an intrinsic synaptic vesicle membrane protein, maps to this target region. Two tightly linked single-nucleotide polymorphisms were recently found in a small subset of patients with SZ - a synonymous variant, L469L (469G>A), and a non-synonymous variant, S470N (470G>A) - which results in the loss of a mitogen-activated protein kinase serine phosphorylation site. We also found a slight increase in 470A in Caucasian patients from the US with schizophrenia. But, the sample size and allele frequency were too small to draw definitive conclusions. However, both single-nucleotide polymorphisms were much more polymorphic in African American controls than in Caucasian controls, thereby providing a better sample cohort to analyze for schizophrenia involvement. For the codon 469 single-nucleotide polymorphisms, a 50-fold increase was observed in the frequency of 469A in African Americans compared with Caucasians. Furthermore, there was an increase in the percentage of African American patients with schizophrenia who were homozygous for the 469A allele compared with controls who were homozygous (11 versus 5%; AA vs. all other genotypes - Fisher statistic=3.08, P=0.04, one-tailed). An increase in 470A heterozygotes was also found, but the results fell short of being statistically significant. The findings support a role for synapsin III in a subset of African American patients with schizophrenia and raises questions about selective pressure in Africa to account for the extraordinary disparity of the 469 and 470 single-nucleotide polymorphisms in different ethnic populations.
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PMID:Association of schizophrenia in African Americans to polymorphism in synapsin III gene. 1590 Feb 27

Gene expression profiles in the cortex of adult Long-Evans rats as a function of a stressful social loss and victory in inter-male fighting encounters were examined. This social dominance and subordination model has been postulated to simulate early changes in the onset of depression in the losers. Microarrays were fabricated containing 45mer oligonucleotides spotted in quadruplicate and representing 1178 brain-associated genes. Dynamic range, discrimination power, accuracy and reproducibility were determined with standard mRNA "spiking" studies. Gene expression profiles in dominant and subordinate animals were compared using a "universal" reference design [Churchill GA (2002) Fundamentals of experimental design for cDNA microarrays. Nat Genet 32 (Suppl):490-495]. Data were analyzed by significance analysis of microarrays using rank scores [Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116-5121; van de Wiel MA (2004) Significance analysis of microarrays using rank scores. Kwantitatieve Methoden 71:25-37]. Ontological analyses were then performed using the GOMiner algorithm [Zeeberg BR, Feng W, Wang G, Wang MD, Fojo AT, Sunshine M, Narasimhan S, Kane DW, Reinhold WC, Lababidi S, Bussey KJ, Riss J, Barrett JC, Weinstein JN (2003) GoMiner: a resource for biological interpretation of genomic and proteomic data. Genome Biol 4(4):R28]. And finally, genes of special interest were further studied using quantitative reverse transcriptase polymerase chain reaction. Twenty-two transcripts were statistically significantly differentially expressed in the neocortex between dominant and subordinate animals. Ontological analyses revealed that significant gene changes were clustered primarily into functional neurochemical pathways associated with protein biosynthesis and cytoskeletal dynamics. The most robust of these were the increased expression of interleukin-18, heat shock protein 27, beta3-tubulin, ribosome-associated membrane protein 4 in subordinate animals. Interleukin-18 has been found to be over-expressed in human depression and panic disorder as well as other physiological stress paradigms [Takeuchi M, Okura T, Mori T, Akita K, Ohta T, Ikeda M, Ikegami H, Kurimoto M (1999) Intracellular production of interleukin-18 in human epithelial-like cell lines is enhanced by hyperosmotic stress in vitro. Cell Tissue Res 297(3):467-473] and heat shock proteins have been shown to be involved in the pathogenesis of many neurodegenerative and psychiatric disorders [Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9(4):406-416; Pongrac JL, Middleton FA, Peng L, Lewis DA, Levitt P, Mirnics K (2004) Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 56(12):943-950]. Thus, the gene expression changes that we have observed here are consistent with and extend the observations found in the clinical literature and link them to the animal model used here thereby reinforcing its use to better understand the genesis of depression and identify novel therapeutic targets for its treatment.
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PMID:Modeling depression: social dominance-submission gene expression patterns in rat neocortex. 1628 86

Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP and decreased striatal DAT-functioning, trying to give a new insight into the pathophysiologically mechanism involved. The hypothesis provides supporting evidence that increased levels of extracellular dopamine in the striatum of DP-patients is likely to be the result of decreased DAT-functioning and not increased rates of release. The hypothesis can be investigated simply by dopamine transporter imaging in patients with DP.
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PMID:Delusional parasitosis and the dopamine transporter. A new insight of etiology? 1713 47

P-Glycoprotein (ABCB1-type P-gp), a membrane protein encoded by the multi drug resistant gene (MDR1), expressing on the blood brain barrier protects the brain from many drugs including dexamethasone. Psychiatric disorders, schizophrenia and depression, have known to have abnormal hypothalamus-pituitary-adrenal (HPA) activity, which is assessed by non-suppression of cortisol in dexamethasone suppression test. The poor response to dexamethasone in these patients' population suggested the impaired activity on dexamethasone penetration into the brain via P-gp, which was associated with MDR1 polymorphisms. We, therefore, examined five SNPs of the MDR1 gene, -1517 T>C (promoter), -41 A>G (intron -1), -129 T>C (exon 1b), 2677 G>A,T (exon 21) and 3435 C>T (exon 26), in Japanese patients with schizophrenia (n=121) and mood disorders (n=62), and compared with the control subjects (n=160). The frequency of MDR1 mutant alleles at -1517, -41 and -129 in patients with mood disorders was significantly lower (2.4, 5.6, 2.4%, respectively) than those of controls (7.8, 13.7, 7.8%, respectively) (p<0.05). The frequencies of MDR1 2677 G/A and A/A genotype in mood disorders was significantly higher (17.7, 6.5%, respectively) than controls (11.2, 0%, respectively) (p<0.05). The 2677A allele frequency in mood disorders (20.2%) was significant higher than controls (10.9%) (p<0.05). Haplotype of 129-2677-3435 (T-A-C) in mood disorders was significantly higher (14.4%) than controls (8.0%) (p<0.05). There was no significant difference in allele and genotype frequencies between the patients with schizophrenia and controls. These findings suggested that predispose to mood disorders, not schizophrenia, was associated with possible alteration of P-gp activities corresponding MDR1 polymorphism at least partly.
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PMID:MDR1 gene polymorphism in Japanese patients with schizophrenia and mood disorders including depression. 1714 80

The synaptosomal-associated protein of 25 kDa (SNAP-25) is a pre-synaptic plasma membrane protein. SNAP-25 plays an important role in synaptic vesicle membrane docking and fusion, which is involved in the regulation of neurotransmitter release. SNAP-25 has been implicated in the pathogenesis of neuropsychiatric disorders including Schizophrenia, attention-deficit hyperactivity disorder and Alzheimer's disease. We cloned a 1584 bp segment of the 5' flanking region of the human SNAP-25 gene. A series of nested deletions of the 5' flanking region fragment were subcloned into the pGL3-basic luciferase reporter plasmid. N2A cells were transfected with the SNAP-25 promoter constructs and luciferase activity was measured as an indication of promoter activity. We identified a 188 bp fragment containing the transcription initiation site as the minimal region necessary for promoter activity. Several putative cis-acting elements including SP1, hypoxia inducible factor (HIF), cAMP-response element binding protein, T-cell factor/lymphocyte enhancer factor 1 (TCF/LEF1), AP1 and the signal transducer and activator of transcription-6 (STAT6) are found in the 5' flanking region of SNAP-25 gene. Transcriptional activation and gel shift assays showed that the human SNAP-25 gene promoter contains functional SP1 response elements. Over-expression of SP1 increased SNAP-25 gene expression and inhibition of SP1-mediated transcriptional activation reduced SNAP-25 gene expression. These results suggest that SP1 plays an important role in regulation of the human SNAP-25 gene expression.
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PMID:SP1 regulates a human SNAP-25 gene expression. 1819 15

The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.
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PMID:Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes. 2007 18

Lanthionine ketimine (LK) represents a poorly understood class of thioethers present in mammalian CNS. Previous work has indicated high-affinity interaction of LK with synaptosomal membrane protein(s), but neither LK binding partners nor specific bioactivities have been reported. In this study, LK was chemically synthesized and used as an affinity agent to capture binding partners from mammalian brain lysate. Liquid chromatography with electrospray ionization-mass spectrometry of electrophoretically separated, LK-bound proteins identified polypeptides implicated in axon remodeling or vesicle trafficking and diseases including Alzheimer's disease and schizophrenia: collapsin response mediator protein-2/dihydropyrimidinase-like protein-2 (CRMP2/DRP2/DPYSL2), myelin basic protein, and syntaxin-binding protein-1 (STXBP1/Munc-18). Also identified was the recently discovered glutathione-binding protein lanthionine synthetase-like protein-1. Functional consequences of LK:CRMP2 interactions were probed through immunoprecipitation studies using brain lysate wherein LK was found to increase CRMP2 coprecipitation with its partner neurofibromin-1 but decreased CRMP2 coprecipitation with beta-tubulin. Functional studies of NSC-34 motor neuron-like cells indicated that a cell-permeable LK-ester, LKE, was nontoxic and protective against oxidative challenge with H(2)O(2). LKE-treated NSC-34 cells significantly increased neurite number and length in a serum concentration-dependent manner, consistent with a CRMP2 interaction. Finally, LKE antagonized the activation of EOC-20 microglia by inflammogens. The results are discussed with reference to possible biochemical origins, paracrine functions, neurological significance, and pharmacological potential of lanthionyl compounds.
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PMID:Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures. 2018 95

Aberrant regulation of synaptic function is thought to play a role in the aetiology of psychiatric disorders, including schizophrenia and bipolar disorder. Normal neurotransmitter release is dependent on a complex group of presynaptic proteins that regulate synaptic vesicle docking, membrane fusion and fission, including synaptophysin, syntaxin, synaptosomal-associated protein-25 (SNAP-25), vesicle-associated membrane protein (VAMP), alpha-synuclein and dynamin I. In addition, structural and signalling proteins such as neural cell adhesion molecule (NCAM) maintain the integrity of the synapse. We have assessed the levels of these important synaptic proteins using Western blots, in three cortical regions (BA10, 40 and 46) obtained post-mortem from subjects with bipolar 1 disorder, schizophrenia or no history of a psychiatric disorder. In bipolar 1 disorder cortex (parietal; BA40), we found a significant increase in the expression of SNAP-25, and a significant reduction in alpha-synuclein compared with controls. These changes in presynaptic protein expression are proposed to inhibit synaptic function in bipolar 1 disorder. In schizophrenia, a significant reduction in the ratio of the two major membrane-bound forms of NCAM (180 and 140) was observed in BA10. The distinct functions of these two NCAM forms suggest that changes in the comparative levels of these proteins could lead to a destabilisation of synaptic signalling. Our data support the notion that there are complex and region-specific alterations in presynaptic proteins that may lead to alterations in synaptic activity in both schizophrenia and bipolar disorder.
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PMID:Region and diagnosis-specific changes in synaptic proteins in schizophrenia and bipolar I disorder. 2048 53


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