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 apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
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PMID:High-resolution SNP scan of chromosome 6p21 in pooled samples from patients with complex diseases. 1270 9

This paper describes the high-throughput proteomic analysis of the dorsolateral prefrontal cortex (DLPFC) from schizophrenia (SCHIZ), bipolar (BD), and normal control cohorts from the Harvard Brain Tissue Resource Center performed using ProteinChip technology based on the surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS). The resultant profiles were utilized in classification-tree algorithms for selection of protein biomarker peaks contributing maximally to the differentiation between the examined diagnostic cohorts. Twenty-four such protein biomarker peaks were identified. All of them had lower levels in the SCHIZ cohort as compared to the BD cohort. Also, 21 of these peaks were down-regulated in the SCHIZ cohort vs. the control cohort, and 7 peaks were up-regulated in the BD cohort vs. the control cohort. The proteins constituting these biomarker peaks were recognized via matrix-assisted laser desorption time of flight/postsource decay mass spectrometry (MALDI-TOF-PSD-MS). These proteins represent a wide range of functional groups involved in cell metabolism, signaling cascades, regulation of gene transcription, protein and RNA chaperoning, and other aspects of cellular homeostasis. Finally, after statistical evaluation suggesting that the selected protein biomarkers are not significantly impacted by epidemiological/tissue storage parameters (although, influence of antipsychotic and mood stabilizing drugs could not be fully excluded), the ProteinChip-based profiling was engaged again to demonstrate that the detected SCHIZ-associated changes in the levels of our protein biomarkers could also be seen in DLPFC samples from the brain collection of the Mount Sinai Medical School/Bronx Veteran Affairs Medical Center. This study demonstrates the usefulness of ProteinChip-based SELDI-TOF protein profiling in gaining insight into the molecular pathology of SCHIZ and BD as it points to changes in protein levels characterizing these diseases.
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PMID:Identification of protein biomarkers for schizophrenia and bipolar disorder in the postmortem prefrontal cortex using SELDI-TOF-MS ProteinChip profiling combined with MALDI-TOF-PSD-MS analysis. 1654 61

Proteomics technologies have been widely used in the investigation of neurodegenerative and psychiatric disorders, and in particular in the detection of differences between healthy individuals and patients suffering from such diseases. Thus, brain and cerebrospinal fluid (CSF) samples from patients with Alzheimer's disease, Down syndrome, Pick's disease, Parkinson's disease, schizophrenia, and other disorders as well as brain and CSF from animals serving as models of neurological disorders have been analyzed by proteomics. 2-DE followed by MALDI-TOF-MS has been mainly applied as this proteomics approach provides the possibility of convenient quantification of protein levels and detection of post-translational modifications. About 330 unique proteins with deranged levels and modifications have been detected by proteomics approaches to be related to neurodegeneration and psychiatric disorders. They are mainly involved in metabolism pathways, cytoskeleton formation, signal transduction, guidance, detoxification, transport, and conformational changes. In this article, we provide a summary of the major contributions of proteomics technologies in the study of neurodegenerative and psychiatric diseases, in particular, in the detection of changes in protein levels and modifications related to these disorders.
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PMID:Proteomics-driven progress in neurodegeneration research. 1655 40

Surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) enables the sensitive, high-throughput protein profiling of complex biological mixtures. In combination with bioinformatics, this technology has the potential to identify combinations of spectral peaks that can differentiate individuals with a particular disease from normal controls. SELDI-TOF-MS was used to screen postmortem tissue derived from the dorsolateral prefrontal cortex of individuals with schizophrenia (n = 34) and matched controls (n = 35), obtained from the Stanley Foundation Neuropathology Consortium. Tissue samples were homogenized in urea buffer, applied to four different chip arrays which possess different chromatographic surfaces, and analyzed using the Ciphergen ProteinChip Biomarkers System (Model PBS II). Protein expression profiles of the schizophrenia and control groups were compared and analyzed using the Ciphergen Express (CE) and Biomarker Patterns Software (BPS) package. We detected several protein peaks whose intensities differed between the schizophrenia and control groups to a highly significant degree. A combination of these peaks was capable of distinguishing between schizophrenia and controls with a sensitivity and specificity of about 70%. The classification model that distinguished schizophrenia from controls was complex, suggesting that the biochemical abnormalities underlying schizophrenia are heterogeneous. Our results suggest that SELDI-TOF-MS has the potential for distinguishing individuals with schizophrenia from normal controls and may eventually lead to a better understanding of the classification, diagnosis and pathogenesis of this disorder.
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PMID:Protein expression profiling of postmortem brain in schizophrenia. 1662 32

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.
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PMID:No association of G72 and D-amino acid oxidase genes with schizophrenia. 1684 73

Over two million Americans are afflicted with schizophrenia, a debilitating mental health disorder with a unique symptomatic and epidemiological profile. Genomics studies have hinted towards candidate schizophrenia susceptibility chromosomal loci and genes. Modern proteomic tools, particularly mass spectrometry and expression scanning, aim to identify both pathogenic-revealing and diagnostically significant biomarkers. Only a few studies on basic proteomics have been conducted for psychiatric disorders relative to the plethora of cancer specific experiments. One such proteomic utility enables the discovery of proteins and biological marker fingerprinting profiling techniques (SELDI-TOF-MS), and then subjects them to tandem mass spectrometric fragmentation and de novo protein sequencing (MALDI-TOF/TOF-MS) for the accurate identification and characterization of the proteins. Such utilities can explain the pathogenesis of neuro-psychiatric disease, provide more objective testing methods, and further demonstrate a biological basis to mental illness. Although clinical proteomics in schizophrenia have yet to reveal a biomarker with diagnostic specificity, methods that better characterize the disorder using endophenotypes can advance findings. Schizophrenia biomarkers could potentially revolutionize its psychopharmacology, changing it into a more hypothesis and genomic/proteomic-driven science.
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PMID:Schizophrenia proteomics: biomarkers on the path to laboratory medicine? 1684 10

Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the gamma isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P=0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P=0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266-rs2272080) and seven-SNP haplotype (rs2461491-rs2469758-rs2461489-rs2469770-rs2449340-rs1482337-rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P<0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P<0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia.
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PMID:More evidence supports the association of PPP3CC with schizophrenia. 1733 75

Repeated administration of methamphetamine (MAP) results in an increased behavioral response to the drug during subsequent exposure. This phenomenon is called behavioral sensitization. Sensitization is an enduring phenomenon, and suggests chronic alterations in neuronal plasticity. MAP-induced sensitization has been proposed and widely investigated as an animal model of MAP psychosis and schizophrenia. However, little is known about the molecular mechanisms underlying MAP-induced sensitization. 2-DE-based proteomics allows us to examine global changes in protein expression in complex biological systems and to propose hypotheses concerning the mechanisms underlying various pathological conditions. In the present study, we examined protein expression profiles in the striatum of MAP-sensitized rats using 2-DE-based proteomics. Repeated administration of MAP (4.0 mg/kg, once a day, intraperitoneal (i.p.)) for 10 days significantly augmented the locomotor response to an MAP challenge injection (1.0 mg/kg, i.p.) on day 11. This enhanced activity was maintained even after a week of drug abstinence. 2-DE analysis revealed 42 protein spots were differentially regulated in the striatum of MAP-sensitized rats compared to control. Thirty-one protein spots were identified using MALDI-TOF, including synapsin II, synaptosomal-associated protein 25 (SNAP-25), adenylyl cyclase-associated protein 1 (CAP1), and dihydropyrimidinase-related protein 2 (DRP2). These proteins can be related to underlying mechanisms of MAP-induced behavioral sensitization, indicating cytoskeletal modification, and altered synaptic function.
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PMID:Protein expression profile in the striatum of rats with methamphetamine-induced behavioral sensitization. 1735 86

Although some insights into the etiology of schizophrenia have been gained, an understanding of the illness at the molecular level remains elusive. Recent advances in proteomic profiling offer great promise for the discovery of markers underlying pathophysiology of diseases. In the present study, we employed two high-throughput proteomic techniques together with traditional methods to investigate cerebrospinal fluid (CSF), brain and peripheral tissues (liver, red blood cells and serum) of schizophrenia patients in an attempt to identify peripheral/surrogate disease markers. The cohorts used to investigate each tissue were largely independent, although some CSF and serum samples were collected from the same patient. To address the major confounding factor of antipsychotic drug treatment, we also included a large cohort of first-onset drug-naive patients. Apolipoprotein A1 (apoA1) showed a significant decrease in expression in schizophrenia patients compared to controls in all five tissues examined. Specifically, using SELDI-TOF mass spectrometry, apoA1 was found decreased in CSF from schizophrenia patients (-35%, P=0.00001) and, using 2D-DIGE, apoA1 was also found downregulated in liver (-30%, P=0.02) and RBCs (-60%, P=0.003). Furthermore, we found a significant reduction of apoA1 in sera of first-onset drug-naive schizophrenia patients using enzyme-linked immunosorbent assay (-18%, P=0.00008) and in two investigations of post-mortem brain tissue using western blot analysis (-35%, P=0.05; -51%, P=0.05). These results show that apoA1 is consistently downregulated in the central nervous system as well as peripheral tissues of schizophrenia patients and may be linked to the underlying disease mechanism.
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PMID:Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues. 1793 34

Schizophrenia is a severe psychotic illness affecting 1% of the general population. There are no consistent pathological features, and the disorder is defined by a complex symptomatology, which overlaps with other psychiatric illnesses. Diagnosis is based on a clinical interview, relying on the patient meeting criteria according to diagnosis manuals, including Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. and International Statistical Classification of Diseases, 10th Revision. Because of the ambiguous symptoms, the diagnostic process can take many months and often years. Rapid and effective treatment has been shown to impact positively on disease progression and outcome, and it is therefore important to identify disease-associated biomarkers allowing early diagnosis. Reliable biomarkers can be used for the development of diagnostic tests and may also help us understand the underlying pathology of this disorder. In the present study, proteins from anti-CD3 stimulated and unstimulated peripheral blood T cell lysates from 15 minimally medicated and unmedicated patients and 15 age-, sex-, race-, and smoking-matched controls were profiled on cation exchange (CM10) chips using SELDI-TOF. Partial least squares discriminate analysis was used to separate patient and control groups according to the expression of 108 detected peaks, and two peaks of 3,374 and 3,450 Da, corresponding to alpha-defensins based on masses and cationic properties, were found to contribute significantly to the separation of patient and control groups. Reduction of T cell lysates with DTT resulted in a 6-Da shift in the mass of these peaks consistent with the presence of three cysteine bonds in the structure, confirming them as alpha-defensins. Quantification of alpha-defensins in T cell lysates from six patients and 18 healthy controls was carried out by ELISA, which also showed that alpha-defensin levels were significantly increased in patient lysates when compared with matched controls (p = 0.0197). Plasma from 21 monozygotic twins discordant for schizophrenia and eight healthy unaffected twin pairs was also analyzed for the expression of alpha-defensins by ELISA. Notably both affected and unaffected twins were found to have significantly elevated alpha-defensin levels compared with healthy control twin pairs (p = 0.0014 and p = 0.0115, respectively). Increased expression of alpha-defensins in unaffected as well as affected discordant monozygotic twins is of particular interest as monozygotic twins share genes and usually environmental upbringing. The unaffected twin therefore represents the biological and environmental risk of developing schizophrenia in the absence of overt symptomatology and therapeutic medication. These findings suggest that alpha-defensins could be an important early indicator of the risk of schizophrenia.
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PMID:Increased alpha-defensins as a blood marker for schizophrenia susceptibility. 1834 40


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