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 strong evidence for the involvement of the neurotransmitter glutamate system in the pathogenesis of Alzheimer's disease and schizophrenia. In these mental diseases, the brain shows changes in the levels of glutamate and in the function and expression of its transporters and receptors. Since the levels of glutamate are largely determined by the rate of its metabolism, the changes of its concentrations may be associated with dysfunctions of appropriate enzymes. Actually, disturbances of glutamate metabolic enzymes, such as glutaminase, glutamate decarboxylase, and glutamine synthetase were detected in the brain of patients with Alzheimer's disease. The alterations in the expression of glutamine synthetase, glutamine synthetase-like protein, and three isoenzymes of glutamate dehydrogenase in the frontal cortex of patients with schizophrenia suggest that there are impaired glutamate metabolism in this mental disease and Alzheimer's disease.
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PMID:[Impaired cerebral glutamate metabolism in mental diseases (Alzheimer's disease, schizophrenia]. 1152 27

Basing primarily on the facts of altered levels of glutamate neurotransmitter, its receptors and transporters in schizophrenic brain, the "glutamatergic hypothesis" of schizophrenia has been broadened into the field of brain glutamate metabolism. Significantly changed levels of glutamine synthetase (GS) and glutamate dehydrogenase (GDH), the key enzymes involved in glutamine-glutamate cycling between neurons and glia, have been found in the prefrontal cortex (area 10) of patients with schizophrenia compared to controls (P<.01). The data were obtained by enzymatic activity determinations as well as immunoreactivity level evaluations for GS, glutamine synthetase-like protein (GSLP), and three GDH isoenzymes in brain extracts by immunoblotting using specific polyclonal and monoclonal antibodies. Inverse changes in amounts of proteins of GS and GSLP, as well as elevation in amounts of GDH isoenzymes have been observed in schizophrenia. The presented results provide evidence for the impairment of glutamate metabolism and, in turn, abnormalities in functioning of the glutamate-glutamine cycle in the frontal cortex of patients with schizophrenia.
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PMID:Glutamine synthetase and glutamate dehydrogenase in the prefrontal cortex of patients with schizophrenia. 1278 56

Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the possible involvement of these genes in the development of paranoid schizophrenia, we genotyped 80 paranoid schizophrenics from northern China and 108 matched controls by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) methods or directly sequencing of PCR product. Seven SNPs were found to be polymorphic in the population investigated. No significant differences in the genotype distributions or allele frequencies between patients and controls were found. Therefore, we conclude the polymorphisms studied in the five genes do not play major roles in pathogenesis of paranoid schizophrenia in the population investigated.
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PMID:An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia. 1564 43

Numerous molecules enable the handling of glutamate that is destined for neurotransmitter release, including transporters, receptors and glutamatergic enzymes. Previous work in our lab has shown altered levels of transcript expression of excitatory amino acid transporters and a vesicular glutamate transporter in the thalamus in schizophrenia. These changes suggest that molecules that facilitate the release and reuptake of glutamate may be abnormal in schizophrenia. In this study we determined the levels of expression of phosphate activated glutaminase (PAG), which converts glutamine to glutamate, and glutamine synthetase (GS), which converts glutamate to glutamine, with the hypothesis that thalamic PAG and GS transcript expression is altered in schizophrenia. We investigated expression of PAG and GS mRNA using in situ hybridization in six different thalamic nuclei (anterior, dorsomedial, centromedial, ventral anterior, ventral and reticular) from 13 persons with schizophrenia and 8 comparison subjects and found that transcripts for PAG and GS were significantly increased in schizophrenia. Increased PAG and GS transcripts suggest enhanced glutamatergic neurotransmission in the thalamus and its efferent targets in schizophrenia.
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PMID:Increased expression of glutaminase and glutamine synthetase mRNA in the thalamus in schizophrenia. 1582 Mar 21

Abnormalities of the anterior cingulate cortex have previously been described in schizophrenia, major depressive disorder and bipolar disorder. In this study 2-DE was performed followed by mass spectrometric sequencing to identify disease-specific protein changes within the anterior cingulate cortex in these psychiatric disorders. The 2-DE system comprised IPGs 4-7 and 6-9 in the first, IEF dimension and SDS-PAGE in the second dimension. Resultant protein spots were compared between control and disease groups. Statistical analysis indicated that 35 spots were differentially expressed in one or more groups. Proteins comprising 26 of these spots were identified by mass spectroscopy. These represented 19 distinct proteins; aconitate hydratase, malate dehydrogenase, fructose bisphosphate aldolase A, ATP synthase, succinyl CoA ketoacid transferase, carbonic anhydrase, alpha- and beta-tubulin, dihydropyrimidinase-related protein-1 and -2, neuronal protein 25, trypsin precursor, glutamate dehydrogenase, glutamine synthetase, sorcin, vacuolar ATPase, creatine kinase, albumin and guanine nucleotide binding protein beta subunit. All but three of these proteins have previously been associated with the major psychiatric disorders. These findings provide support for the view that cytoskeletal and mitochondrial dysfunction are important components of the neuropathology of the major psychiatric disorders.
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PMID:Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease-associated changes. 1663 10

According to contemporary views, the glutamatergic system is implicated in the pathogenesis of schizophrenia, and atypical neuroleptics exert their effects (at least partially) through the glutamatergic system. Immunoreactive glutamate-metabolising enzymes, such as glutamine synthetase-like protein (GSLP) and two glutamate dehydrogenase isoenzymes (GDH), have been discovered in human platelets. The amount of GSLP in the platelets of 40 chronic patients with schizophrenia was found to be significantly higher than in 33 controls (consistent with our previous finding of increased amounts of GSLP in the prefrontal cortex of chronic schizophrenia patients). Moreover, survival analysis of the group of patients treated with olanzapine for 28 weeks showed that the larger amount of GSLP measured in platelets before treatment, the shorter the treatment time needed to achieve a positive clinical response (defined a priori as > or = 20% reduction in PANSS total score from the initial level before the treatment). Hence, GSLP level may serve as a predictor of the treatment duration to achieve a positive outcome with olanzapine. Both GSLP and GDH were found significantly changed in the course of treatment; hence, treatment with olanzapine influences the amounts of glutamate-metabolising enzymes in the platelets of chronic schizophrenia patients.
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PMID:Effect of olanzapine treatment on platelet glutamine synthetase-like protein and glutamate dehydrogenase immunoreactivity in schizophrenia. 1668 79

Several theories of schizophrenia suggest dysfunction in glutamate neurotransmission in higher brain regions such as the prefrontal cortex (PFC). Previous studies have investigated whether astroglial abnormalities could give rise to glutamate dysfunction using glial fibrillary acidic protein (GFAP) immunocytochemistry. We have used quantitative immunoautoradiography to measure glutamine synthetase (GS), the glial enzyme which recycles synaptic glutamate, as a more direct test of glial mechanisms of abnormal glutamate function in schizophrenia. We compared GS with GFAP immunoautoradiography in dorsolateral (area 9) and orbitofrontal (area 11/47) cortex. Optical density measures from film autoradiographs revealed an increase in GFAP immunoreactivity in area 9 in schizophrenia and a decrease in area 11/47 in both schizophrenia and bipolar disorder. The increase in GFAP in area 9 significantly correlated with lifetime antipsychotic drug treatment, whereas the reduction in area 11/47 occurred despite this effect. There were no changes in GS immunoreactivity in any psychiatric disorder. Regional and antigen-specific down-regulation of GFAP protein in OFC in schizophrenia and bipolar disorder may relate to disease mechanisms of psychosis.
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PMID:Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. 1684 14

We have used a systemic approach to establish a relationship between enzyme measures of glial glutamate and energy metabolism (glutamine synthetase and glutamine synthetase-like protein, glutamate dehydrogenase isoenzymes, brain isoform creatine phosphokinase) and two major glial proteins (glial fibrillary acidic protein and myelin basic protein) in autopsied brain samples taken from patients with schizophrenia (SCH) and mentally healthy subjects (23 and 22 cases, respectively). These biochemical parameters were measured in tissue extracts in three brain areas (prefrontal cortex, caudate nucleus, and cerebellum). Significant differences in the level of at least one of the glutamate metabolizing enzymes were observed between two studied groups in all studied brain areas. Different patterns of correlative links between the biochemical parameters were found in healthy and schizophrenic brains. These findings give a new perspective to our understanding of the impaired regulation of enzyme levels in the brain in SCH.
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PMID:Systemic neurochemical alterations in schizophrenic brain: glutamate metabolism in focus. 1744 Aug 11

Relative amounts of the glutamate metabolizing enzymes - glutamine synthetase, glutamine synthetase-like protein, three isoenzymes of glutamate dehydrogenase as well as creatine phosphokinase (a main astroglial energy metabolism enzyme) and major proteins of astro- and oligodendroglia - a glial fibrillary acidic protein and a myelin basic protein were determined in postmortem brain extracts from three areas - the prefrontal cortex, caudate nucleus and cerebellum - from mentally healthy subjects (n=21) and patients with chronic schizophrenia (n=23). To single out "metabolic types" the data obtained have been subjected to cluster analysis. It has been demonstrated for the first time that the cluster analysis of the biological parameters (enzymes and proteins) with correction for age, gender, postmortem interval and presence/absence of diagnosis, enables to distinguish "mentally healthy" cases and "schizophrenic patients" with a high degree of significance (mean mixing error <20%, small er, Cyrillic>>0,00004). Thus, we suppose that mentally healthy controls and patients with schizophrenia are objectively divided into different "metabolic types".
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PMID:[The complex neurochemical assessment of brain proteins in mentally healthy subjects and schizophrenic patients]. 1842 2

Altered expression of structural and functional molecules expressed by astrocytes may play a role in the pathophysiology of schizophrenia. We investigated the hypothesis that the astrocytic enzyme glutamine synthetase, involved in maintaining the glutamate-glutamine cycle, and the cytoskeletal molecule glial fibrillary acidic protein (GFAP) are abnormally expressed in schizophrenia. We used Western blot analysis to measure levels of glutamine synthetase and GFAP in several brain regions of subjects with schizophrenia and a comparison group. We found that glutamine synthetase protein expression was significantly decreased in the superior temporal gyrus, and both glutamine synthetase and GFAP were significantly reduced in the anterior cingulate cortex in schizophrenia. Neither molecule demonstrated altered expression in the dorsolateral prefrontal cortex, primary visual cortex, or hippocampus. Chronic treatment with haloperidol did not alter the expression of these molecules in the rat brain, suggesting that our findings are not due to a medication effect. These data support an astrocytic component to the pathophysiology of schizophrenia and suggest that astrocytic molecules involved in enzymatic activity and cytoskeletal integrity may have a role in disease-related abnormalities in this illness.
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PMID:Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. 1856 76


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