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)

There is mounting evidence, primarily from research in experimental animals, that the dipeptide N-acetylaspartylglutamate (NAAG) and its metabolic enzyme, N-acetylated alpha-linked acid dipeptidase (NAALADase), are involved in glutamatergic neurotransmission. Previous studies in neuropsychiatric disorders associated with the dysregulation of glutamatergic neurotransmission, such as schizophrenia, seizure disorders, and amyotrophic lateral sclerosis (ALS), have revealed region-specific alterations in the levels of NAAG and in the activity of NAALADase. To establish better the cellular localization of these and related parameters in human brain, we have examined their alterations in two well-characterized selective neurodengenerative disorders, Huntington Disease (HD) and Alzheimer Disease (AD). Brain regions from postmortem controls and HD- or AD-affected individuals were assayed to determine the activity of NAALADase as well as the levels of NAAG, N-acetylaspartate (NAA), and several amino acids. The relationships between changes in these neurochemical parameters and changes in neuronal and glial cell density were determined. The present report demonstrates that the decreases in the levels of NAAG and NAA and in the activity of NAALADase in AD and HD brain correlate primarily with neuronal loss. By inference, the results suggest that NAAG and NAA have primarily a neuronal localization in human brain and that there is a close relationship between NAAG and the dipeptidase NAALADase in populations of affected neurons.
Mol Chem Neuropathol 1997 Jun
PMID:N-acetylaspartylglutamate, N-acetylaspartate, and N-acetylated alpha-linked acidic dipeptidase in human brain and their alterations in Huntington and Alzheimer's diseases. 937 25

Aromatic L-amino acid decarboxylase (AADC) is rate limiting in the production of 2-phenylethylamine (2PE). AADC activity and 2PE serum concentrations have been found to be increased in schizophrenic patients. Both antipsychotic and psychotogenic drugs, including amphetamine, affect the activity and encoding mRNA levels of AADC. Amphetamine is an analogue of 2PE and has a similar physiological effect. We have looked at the effects of chronic (32 day) treatment of rats with LSD (0.12 microg/kg/day) and phencyclidine (PCP; 10 mg/kg/day) on AADC mRNA levels. Both drugs up-regulated AADC mRNA levels in striatum, nucleus accumbens, hippocampus and cerebellum by between 50% and 150%. A splicing variant of AADC, present in human brain, which lacks the 3rd exon does not appear to be present in rat brain. These results are consistent with the hypothesis that over activity of AADC leading to increased production of 2PE is involved in endogenous psychosis such as schizophrenia.
Brain Res Mol Brain Res 1997 Oct 03
PMID:Does phenylethylamine have a role in schizophrenia?: LSD and PCP up-regulate aromatic L-amino acid decarboxylase mRNA levels. 938 86

Several recent studies have suggested that expanded CAG repeats may contribute to the genetic transmission of bipolar disorder and schizophrenia. In all known disorders associated with expanded CAG repeats, the repeat sequence is translated into glutamine. Therefore the simplest hypothesis is that one or more proteins with expanded polyglutamine sequences are involved in the pathogenesis of bipolar disorder and schizophrenia. In order to examine this hypothesis, we have used an antibody against expanded polyglutamine sequences to examine Western blots prepared from lymphoblastoid cell lines of patients with schizophrenia and bipolar disorder. We also examined Western blots prepared from left frontal cortex tissue samples obtained from 11 schizophrenics post mortem. With the exception of the TATA-binding protein (TBP), we did not detect any proteins containing expanded polyglutamine sequences. Our data therefore suggest either that the expanded repeats which are associated with these disorders do not encode polyglutamine, or that they are within genes that are not expressed within the tissues investigated here.
Mol Psychiatry
PMID:No evidence for expanded polyglutamine sequences in bipolar disorder and schizophrenia. 939 91

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in psychiatric disorders. Notably, opioid peptide immunoreactivity is altered in the cerebrospinal fluid of chronic schizophrenics and manic-depressive subjects. Despite these clinical findings, few postmortem investigations have examined the association of endogenous opioid neuropeptides with schizophrenia and suicide. Anatomically, a tight interaction exists within the neostriatum between the opioid peptide (dynorphin and enkephalin) system and classical neurotransmitters such as dopamine which has been implicated in both the psychotic symptoms and the cognitive deficits that characterize schizophrenia (see review). The neostriatum is differentially organized into patch and matrix neurochemical mosaic compartments anatomically connected to limbic- and sensorimotor-related brain regions, respectively. Moreover, the human neostriatum is characterized by a heterogenous expression of the prodynorphin opioid gene: high in the patch, but low in the matrix compartment. The present results show for the first time a differential alteration of prodynorphin within distinct striatal compartments in postmortem tissue from nonschizophrenic suicide subjects. The prodynorphin patch/matrix mRNA expression was elevated in the caudate nucleus of suicide subjects as compared to normal controls and schizophrenics in which no alterations in opioid peptides or D1 and D2 mRNA expression were apparent. Altogether the findings suggest that discrete dysfunction of the endogenous opioid dynorphin system might contribute to depression and the risk of suicide in nonschizophrenic subjects.
Mol Psychiatry
PMID:Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects. 939 95

Based on anatomical and biochemical observations a role of glutamate in schizophrenia has been postulated. In the present work we have investigated the gene expression for two families of NMDA receptor subunits (NR-1 and NR-2) following acute and chronic treatment with typical (haloperidol) and atypical (clozapine) antipsychotic drug (APD) in rats. A single injection of the two drugs elicited a significant increase in the mRNA levels of NR-2B in the nucleus accumbens, whereas only haloperidol was able to elevate NR-2A and NR-2B in the hippocampus. Following a 21 day treatment, significant differences in the regulatory pattern of NMDA-R subunits were observed. Haloperidol increased their mRNA levels in striatum whereas clozapine, consistent with its relatively weaker influence on nigro-striatal dopamine function, did not change the expression of NR subunits in this region. Both APD's were able to decrease the expression of NR-2 subunits in the hypothalamus, but only clozapine was capable of reducing NR-2C in frontal cortex and accumbens. The regulation of NMDA-R subunits in specific brain regions may represent a novel and important mechanism through which APD's exert some of their effects on brain function.
Brain Res Mol Brain Res 1997 Oct 15
PMID:Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs. 940 28

To date, the molecular biology of and the genes responsible for schizophrenia are unknown. However, the powerful techniques for gene mapping and mutation analysis now available mean the situation should change and it is likely that a variety of genes involved in schizophrenia are likely to be mapped, cloned and characterized within the next few years. Initial over-optimism should not be replaced by pessimism as to the future prospects.
Mol Cell Biol Hum Dis Ser 1994
PMID:Molecular biology of schizophrenia. 943 48

The D4 dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. 32P-labelled RNA probes to the D4 DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P<0.011) of D4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D4 receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia.
Brain Res Mol Brain Res 1998 Jan
PMID:Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. 947 18

Many human hereditary neurodegenerative diseases are caused by expanded CAG repeats, and anonymous CAG expansions have also been described in schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activated potassium channel (hSKCa3) that contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allele frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcoxon Rank Sum test, P=0.024), with CAG repeats longer than the modal value being over-represented in patients (Fisher Exact test, P=0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible association between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated K+ channels play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.
Mol Psychiatry 1998 Jan
PMID:Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? 949 10

Several studies have shown an association between schizophrenia and the C allele of a T-C polymorphism at nucleotide 102 and the 5HT2A receptor gene. In the present study we observed this association in a sample of 63 parent/offspring trios where the proband received a diagnosis of DSM-III-R schizophrenia using TDT analysis (chi2 = 6.26, P= 0.006, chi2 = 9.00, P=0.001 when one affected offspring was selected at random from each family, suggesting that the results are due to association rather than linkage). There was no significant difference between the transmission of C102 from heterozygous fathers and mothers, which fails to support a role for genomic imprinting in this effect. T102C does not result in an alteration of the amino acid sequence of the protein. We therefore screened the promoter of 5HT2A for polymorphisms using single-strand confirmation polymorphism analysis. An A-G polymorphism at -1438 that creates an HpaII restriction site was identified. This was found to be in complete linkage disequilibrium with T102C and is hence a candidate for the pathogenic variant in schizophrenia. Functional analysis of A-1438G using luciferase assay demonstrated significant basal promoter activity in 5HT2A expressing HeLa cells by both the A and G variants. However, comparison of the A and G variants showed no significant differences in basal activity nor when promoter activity was induced by cAMP and protein kinase C-dependent mechanisms.
Mol Psychiatry 1998 Jan
PMID:A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. 949 12

The evidence for a significant genetic contribution to the functional psychoses (schizophrenia and bipolar disorder) is now well established. However, in both cases, the non-mendelian mode of inheritance has made the identification of susceptibility loci particularly challenging. The neuropeptide cholecystokinin (CCK) is present both in the gut and the CNS. Studies of CCK-like immunoreactivity and CCK mRNA levels in human brains have revealed high concentrations in numerous loci and shown colocalisation of CCK with, for example, dopamine and tyrosine hydroxylase. Furthermore, antagonists of CCK-B receptors, which are found most frequently in the brain, inhibit the activity of brain dopamine neurons. Such findings suggest that, with respect to neuropsychiatric disorders, CCK is a suitable candidate for analysis using methods to detect gene variations which have the potential to affect protein structure or expression. In the present study, mutation analyses were carried out on the human CCK gene. Linked polymorphisms were found in the promoter region and in intron 1 close to the 3' mRNA splice acceptor site. However, the allele frequencies of these polymorphisms in samples of individuals affected with either schizophrenia (n=117) or bipolar disorder (n=124) did not differ from those of control subjects (n=234), suggesting that these variations do not confer a predisposition to either of the functional psychoses.
Mol Psychiatry 1998 Jan
PMID:Linked polymorphisms upstream of exons 1 and 2 of the human cholecystokinin gene are not associated with schizophrenia or bipolar disorder. 949 15


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