Proteins In Schizophrenia Research Articles

Mendelian randomization analysis of causal and druggable circulating inflammatory proteins in schizophrenia.

Schizophrenia (SZ) is a severe mental disorder with complex origins. Observational studies suggested that inflammatory factors may play a role in the pathophysiology of SZ and we aim to investigate the potential genetic connection between them by examining the causal impact of circulating inflammatory proteins on SZ. We utilized Mendelian randomization (MR) analysis to assess the causal relationship between circulating inflammatory proteins and SZ and the GWAS summary datasets were sourced from public databases. The SZ dataset comprised 74,776 cases and 101,023 controls, while the summary results for 91 plasma proteins in 14,824 participants were obtained through the Olink Target platform. Moreover, to identify and evaluate potential drug targets, we searched the Drug-Gene Interaction Database (DGIdb). The results of the MR study confirmed that nine inflammatory proteins had a causal effect on SZ. Among these proteins, IL1A (OR: 0.93), TNFB (OR: 0.94), TNFSF14 (OR: 0.96), and CD40 (OR: 0.95) exhibited protective effects against SZ. Conversely, CCL23 (OR: 1.04), CCL19 (OR: 1.04), 4EBP1 (OR: 1.06), TWEAK (OR: 1.08), and DNER (OR: 1.10) were associated with an increased risk of SZ. The MR-Egger and weighted median methods also supported the direction of these effects. According to the Gene-Drug analysis, LTA, IL1A, CD40, and 4EBP1 can serve as drug targets. Our study established causal relationships between circulating inflammatory proteins and SZ. It may be beneficial to personalize the treatment of SZ by incorporating inflammation management into the treatment regimen.

Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach.

Investigating the shared brain protein and genetic components of schizophrenia (SCZ) and bipolar I disorder (BD-I) presents a unique opportunity to understand the underlying pathophysiological processes and pinpoint potential drug targets. To identify overlapping susceptibility brain proteins in SCZ and BD-I, we carried out proteome-wide association studies (PWAS) and Mendelian Randomization (MR) by integrating human brain protein quantitative trait loci with large-scale genome-wide association studies for both disorders. We utilized transcriptome-wide association studies (TWAS) to determine the consistency of mRNA-protein dysregulation in both disorders. We applied pleiotropy-informed conditional false discovery rate (pleioFDR) analysis to identify common risk genetic loci for SCZ and BD-I. Additionally, we performed a cell-type-specific analysis in the human brain to detect risk genes notably enriched in distinct brain cell types. The impact of risk gene overexpression on dendritic arborization and axon length in neurons was also examined. Our PWAS identified 42 proteins associated with SCZ and 14 with BD-I, among which NEK4, HARS2, SUGP1, and DUS2 were common to both conditions. TWAS and MR analysis verified the significant risk gene NEK4 for both SCZ and BD-I. PleioFDR analysis further supported genetic risk loci associated with NEK4 for both conditions. The cell-type specificity analysis revealed that NEK4 is expressed on the surface of glutamatergic neurons, and its overexpression enhances dendritic arborization and axon length in cultured primary neurons. These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.

Plasma G72 protein in schizophrenia: A comparative analysis of drug-naive schizophrenia patients, patients in acute exacerbation and healthy controls

ObjectivesSchizophrenia is a complex psychiatric disorder with an unclear etiopathogenesis. This study investigates the plasma G72 protein levels in drug-naive schizophrenia patients (DNS), those in acute psychotic episodes (AES), and healthy controls (HC). It also examines the correlation between the plasma G72 protein levels and Positive and Negative Syndrome Scale (PANSS) scores. MethodsThe study included 138 schizophrenia patients (84 DNS, 54 AES) and 83 HCs. Plasma G72 protein levels were measured by ELISA. Statistical analyses, including log-transformation and correlation analysis, were conducted. ResultsSchizophrenia patients had significantly lower plasma G72 levels than HCs (4.39 ± 5.38 vs. 8.06 ± 10.27 ng/mL, p < 0.001), while DNS and AES groups did not differ significantly. Log-transformed data confirmed these differences. Negative correlation was found between plasma G72 levels and age (r = −0.258, p = 0.02), PANSS-G (r = −0.249, p = 0.004), and total PANSS scores (r = −0.226, p = 0.008). ROC analysis showed poor discrimination between schizophrenia patients and controls (AUC: 0.587, p = 0.031). ConclusionsThis study's novel findings reveal that plasma G72 protein levels are significantly lower in schizophrenia patients and inversely correlated with age and symptom severity. However, the poor diagnostic accuracy observed in the ROC analysis suggests that G72 may not be a reliable biomarker for schizophrenia at this stage. These results underscore the need for further research to explore the potential clinical implications of these findings.

Associations between prefrontal PI (16:0/20:4) lipid, TNC mRNA, and APOA1 protein in schizophrenia: A trans-omics analysis in post-mortem brain.

Though various mechanisms have been proposed for the pathophysiology of schizophrenia, the full extent of these mechanisms remains unclear, and little is known about the relationships among them. We carried out trans-omics analyses by comparing the results of the previously reported lipidomics, transcriptomics, and proteomics analyses; all of these studies used common post-mortem brain samples. We collected the data from three aforementioned omics studies on 6 common post-mortem samples (3 schizophrenia patients and 3 controls), and analyzed them as a whole group sample. Three correlation analyses were performed for each of the two of three omics studies in these samples. In order to discuss the strength of the correlations in a limited sample size, the p-values of each correlation coefficient were confirmed using the Student's t-test. In addition, partial correlation analysis was also performed for some correlations, to verify the strength of the impact of each factor on the correlations. The following three factors were strongly correlated with each other: the lipid level of phosphatidylinositol (PI) (16:0/20:4), the amount of TNC mRNA, and the quantitative signal intensity of APOA1 protein. PI (16:0/20:4) and TNC showed a positive correlation, while PI (16:0/20:4) and APOA1, and TNC and APOA1 showed negative correlations. All of these correlations reached at p < 0.01. PI (16:0/20:4) and TNC were decreased in the prefrontal cortex of schizophrenia samples, while APOA1 was increased. Partial correlation analyses among them suggested that PI (16:0/20:4) and TNC have no direct correlation, but their relationships are mediated by APOA1. The current results suggest that these three factors may provide new clues to elucidate the relationships among the candidate mechanisms of schizophrenia, and support the potential of trans-omics analyses as a new analytical method.

The response to unfolded proteins in schizophrenia and bipolar disorder

IntroductionSchizophrenia (SCH) and bipolar disorder (BD) are severe mental disordes, which have high incidence (Whiteford et al. Lancet 2013; 381 1575-86) and are the main causes of diasibility in young people (WHO 2022; https://www.who.int/news-room/fact-sheets/detail/mental-disorders).Psycological stress appears in different mental disorders, and this is directly related to oxidative stress (Moller et al. Chem Biol Interact. 1996; 102 17-36)(Pupic-Bakrac et al. 2020; Psychiatr Danub. 32 412-9). Oxidative stress causes reticulum edoplasmic stress (ER stress) and this produces high levels of misfolded proteins. Defective proteins are degraded by the proteasome, but but when the density of misfolded proteins exceeds the capacity of the proteosome, the Unfolded and Misfolded Protein Response (UPR) is triggered through three main pathways: Inositol-requiring enzyme 1α (IRE1α); transcription factor 6 alpha (ATF6α) and protein kinase RNA-Like ER kinase (PERK), trying to recover normal protein synthesis capacity (Bermejo-Millo et al. 2018; Mol Neurobiol. 55 7973-86) (González-Blanco et al. 2022; J Cachexia Sarcopenia Muscle 13 919-31).ObjectivesCharacterizing ER stress and UPR in SCH and BD.MethodsWe studied ER stress and UPR in peripheral blood mononuclear cells (PBMC) from 50 patients with SCH and an equal number of patients with BD compared to their corresponding controls in order to achieve our objectives.Western Blot assay were performed following classical procedure () and the results was normalized to Ponceau as loanding control (Nie et al. 2017; BiochemByophys Resp 12 10-13) (Sander et al. 2019; Anal Biochem 575 44-53). Proteasome activity was assessed using Proteasome Activity Assay Kit (ab107921, Abcam, Cambridge, UK).ResultsER stress was evaluated with BiP/GRP78. Our results showed significantly increased expression in SCH (p&lt;0,01) and BD (p&lt;0,05), being more increased in SCH. Proteasome activity was increased in SCH and BD, being only statistically significant in SQZ (p&lt;0,05). UPR study showed IRE1a cascade significantly activated in SCH (p&lt;0,001) and only slight increased in BD showed without statistical differences. ATF6a pathway is measured by cleavage to active protein (50-kDa). Results showed higher expression in SCH than in BD and controls (p&lt;0,001). In addition, PERK pathway showed higher statistical levels of p-eIF2a/eiF2a ratio in SCH than in BD and control respectively (p&lt;0,05 and p&lt;0,01).ConclusionsOur results showed a greater alteration in SCH than in BD at the level of protein synthesis, which implies a greater toxicity at the cellular level and, therefore, a clear risk for the survival of cells in this pathology.Disclosure of InterestNone Declared

Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

Schizophrenia (SZ) is a psychiatric disorder with complex genetic risk dictated by interactions between hundreds of risk variants. Epigenetic factors, such as histone posttranslational modifications (PTMs), have been shown to play critical roles in many neurodevelopmental processes, and when perturbed may also contribute to the precipitation of disease. Here, we apply an unbiased proteomics approach to evaluate combinatorial histone PTMs in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons from individuals with SZ. We observe hyperacetylation of H2A.Z and H4 in neurons derived from SZ cases, results that were confirmed in postmortem human brain. We demonstrate that the bromodomain and extraterminal (BET) protein, BRD4, is a bona fide ‘reader’ of H2A.Z acetylation, and further provide evidence that BET family protein inhibition ameliorates transcriptional abnormalities in patient-derived neurons. Thus, treatments aimed at alleviating BET protein interactions with hyperacetylated histones may aid in the prevention or treatment of SZ.

The D2R-DISC1 protein complex and associated proteins are altered in schizophrenia and normalized with antipsychotic treatment.

BackgroundFor decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 (DISC1) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia.MethodsWe used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples.ResultsLevels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment.LimitationsSample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands.ConclusionLevels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia.

Expression Analysis of 4-Hydroxynonenal Modified Proteins in Schizophrenia Brain; Relevance to Involvement in Redox Dysregulation

Background: Oxidative damage contributes to the pathophysiology of schizophrenia (SZ). Redox imbalance may lead to increased lipid peroxidation, which produces toxic aldehydes like 4-hydroxynonenal (4-HNE) ultimately leading to oxidative stress. Conversely, implications of oxidative stress points towards an alteration in HNE-protein adducts and activities of enzymatic and antioxidant systems in schizophrenia. Objectives: Present study focuses on identification of HNE-protein adducts and its related molecular consequences in schizophrenia pathology due to oxidative stress, particularly lipid peroxidation. Material and Methods: Oxyblotting was performed on seven autopsied brain samples each from cortex and hippocampus region of schizophrenia patients and their respective normal healthy controls. Additionally, thiobarbituric acid substances (TBARS), reduced glutathione (GSH) levels and catalase (CAT) activities associated with oxidative stress, were also estimated. Results: Obtained results indicates substantially higher levels of oxidative stress in schizophrenia patients than healthy control group represented by elevated expression of HNE-protein adducts. Interestingly, hippocampus region of schizophrenia brain shows increased HNE protein adducts compared to cortex. An increase in catalase activity (4.8876 ± 1.7123) whereas decrease in antioxidant GSH levels (0.213 ± 0.015µmol/ml) have been observed in SZ brain. Elevated TBARS level (0.3801 ± 0.0532ug/ml) were obtained in brain regions SZ patients compared with their controls that reflects an increased lipid peroxidation (LPO). Conclusion: Conclusion: We propose the role of HNE modified proteins possibly associated with the pathology of schizophrenia. Our data revealed increase lipid peroxidation as a consequence of increased TBARS production. Furthermore, altered cellular antioxidants pathways related to GSH and CAT also highlight the involvement of oxidative stress in schizophrenia pathology.

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood–brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study

ObjectiveThe mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (VND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [11C]-PBR28 and used an occupancy plot to quantify VND in patients with schizophrenia.MethodsA total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [11C]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (VND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the VND at a single subject level using the SIME method.ResultsAll patients showed a global and generalized reduction in [11C]PBR28 uptake after the administration of XBD173. Constraining the VND to be equal for all patients, the population VND was estimated to be 1.99 mL/cm3 (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar.ConclusionsIn schizophrenia patients, a substantial component of the [11C]PBR28 signal represents specific binding to TSPO. Furthermore, the VND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.

Changes in the Brain Extracellular Matrix Composition in schizophrenia: A Pathophysiological Dysregulation and a Potential Therapeutic Target.

The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography-tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (P = 0.0166), SPARC (P = 0.0003), lumican (P = 0.0012), and nidogen-1 (P < 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ.

Serum Concentration of S100B as Prognostic Parameter in Acute Schizophrenia Patients

Schizophrenia (SZ) is an ongoing mental issue portrayed by certain (e.g., pipedreams and fancies) ,negative (e.g., indifference and disabled inspiration), and psychological symptoms(e.g., lackluster showing in leader fu/nctions and consideration). S100B protein has been one of the most habitually examined proteins in schizophrenia. A few examinations have highlighted an expected part of s100B in SZ ,with most investigations detailing modified fringe levels of s100B when contrasted and sound controls,the point of this work is to decide serum level of S100B in an example of intense schizophrenic patients. Additionally to analyze the serum levels of s100B in schizophrenic patients and solid controls and to examine a potential relationship between's them. This scientific (case control) study included fifty patients intense schizophrenia and a comparative number of typical sound people as control gathering. The two gatherings were exposed to a semi organized meeting, SCID,PANSS and serum level of s100B.

T181. PROTEIN ACYL-THIOESTERASE ENZYME ACTIVITY IN THE POSTMORTEM DORSOLATERAL PREFRONTAL CORTEX IN SCHIZOPHRENIA

BackgroundThe role protein trafficking and localization is a recent target of investigation in schizophrenia pathophysiology. An important mediator of protein trafficking is S-acylation, also known as S-palmitoylation, which is the reversible attachment of long chain fatty acids to cysteine residues. S-acylation is a dynamic post-translational modification that modulates hydrophobicity of proteins, regulating their membrane association and subcellular localization. Notably, we have previously reported a proteome-wide decrease in S-acylated protein levels in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. One potential mechanism of decreased S-acylation is increased removal of acyl groups from proteins by protein acyl-thioesterase enzymes (PATs). Here we describe the optimization of an assay to measure the activity of the PAT family of enzymes in human postmortem cortical tissue and use the assay to address our hypothesis that PAT activity is increased in the DLPFC of subjects with schizophrenia.MethodsTo determine PAT activity, tissue homogenate was incubated with 4-methylumbelliferyl-6-thio-palmitate-β-D-glucopyranoside (4MU-Gluc-Palm) and 1U of exogenous β-glucosidase (to hydrolyze the 4MU-Gluc reaction intermediary). Released 4MU was excited at 360 ± 40 nm and fluorescent emission was measured, per minute, at 460 ± 40 nm. To determine the relationship between initial reaction rate and amount of enzyme, the initial reaction rate using 300 µM 4MU-Gluc-Palm was measured in homogenate containing 1 – 10 µg of total protein from the DLPFC of a subject with no history of psychiatric illness. The PAT activity of DLPFC homogenate boiled for 30 min and total protein homogenate from lymphocytes were measured as negative and positive control reactions, respectively.To estimate the maximum reaction rate (Vmax) and the concentration of 4MU-Gluc-Palm which achieved ½ Vmax (Km; a measure of enzyme-substrate affinity) the initial reaction rate was calculated in the presence of 0 – 200 µM 4MU-Gluc-Palm and the Michaelis-Menten equation was fit to plots of concentration vs. initial rate. Reactions were performed on 2.5 µg total protein homogenate from the DLPFC of 24 subjects with schizophrenia and 24 non-psychiatrically ill subjects.ResultsA fluorescent signal, which increases with time to a plateau upon substrate depletion, is detectable in total protein homogenate from DLPFC and lymphocytes, but not boiled DLPFC homogenate. In the DLPFC the initial reaction rate is linear with total protein amount [r2 = .99; p = .007], demonstrating that the reaction is sensitive to varying amounts of enzyme in a 10-fold range. When compared between schizophrenia and control subjects, neither Vmax [t(46) = 0.756; p = .45] nor Km [t(46) = 0.780; p = .44] were statistically significantly different.DiscussionHere we have demonstrated that PAT activity is measurable in human cortical tissue homogenate. Additionally, we have found no difference in the Vmax or Km of the combined PAT enzyme group in schizophrenia, providing no evidence to support our hypothesis that total PAT activity is increased in subjects with schizophrenia. This suggests that the proteome-wide decrease in S-acylated proteins in schizophrenia is caused by another mechanism, possibly increased expression or function of one or more of the specific PATs, leading to substrate specific changes in S-acylation, or a decrease in activity the acyl protein transferase enzymes, which attach acyl groups to proteins.

Zinc finger proteins in psychiatric disorders and response to psychotropic medications.

Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

32.1 MECHANISMS OF ABNORMAL POSTTRANSLATIONAL PROTEIN PROCESSING IN SCHIZOPHRENIA BRAIN

32.1 MECHANISMS OF ABNORMAL POSTTRANSLATIONAL PROTEIN PROCESSING IN SCHIZOPHRENIA BRAIN

32. DIGGING DEEPER IN THE PROTEOME OF SCHIZOPHRENIA

Overall : Advances in genomics and transcriptomics have yielded novel insights for the pathophysiology of schizophrenia, moving the field forward by providing new substrates for the development of treatment strategies. Interestingly, this has led to a large gap in knowledge in the field, as the impact of genomic variability or alterations in transcript expression is dependent on the next level of gene expression. While proteomics has lagged behind other disciplines in schizophrenia research, several groups are utilizing proteomics approaches to ask and answer the largest possible questions in translational schizophrenia research. Proteomics has evolved as a field very quickly, going beyond the characterization of expression levels of one or a few proteins. With precise quantification of protein expression and degradation, characterization of post-translational modifications as well as the detection of low abundant proteins as putative biomarkers, we will show several different state-of-the-art proteomics approaches applied to the schizophrenia substrate. James Meador-Woodruff (University of Alabama at Birmingham) will provide a brief overview of the field, and present new data showing abnormalities of lipid and carbohydrate modifications on receptor proteins in schizophrenia, as well as abnormal levels of key enzymes associated with these abnormal protein modifications. Robert McCullumsmith (University of Cincinnati, USA) will add pivotal information on the long-standing synaptic hypothesis of schizophrenia by depicting the PSD95 interactome in normal and schizophrenia brain, connecting the excitatory postsynaptic proteome to Big Data analytics. The other two speakers will show have translational proteomics data can be used to develop clinical biomarkers. Dr. Mariana Fioramonte will present how the use of the latest tools in proteomics can tell us more about brain proteomics and protein interactomics. Finally, David Cotter (Royal College of Surgeons, Ireland) will show that proteins associated to the complement system present in the blood plasma of adolescent subjects experiencing psychosis can be predictive broadly in the vulnerability of adult psychiatric disorders. This symposium provides relevant on the biological and biochemical aspects of schizophrenia and proposes potential applications that might be, after adjustments and validations, implemented in the clinic in the future, towards a personalized medicine concept.

Abnormal expression of ER quality control and ER associated degradation proteins in the dorsolateral prefrontal cortex in schizophrenia

Abnormalities in posttranslational protein modifications (PTMs) that regulate protein targeting, trafficking, synthesis, and function have been implicated in the pathophysiology of schizophrenia. The endoplasmic reticulum (ER) contains specialized machinery that facilitate protein synthesis, ER entry and exit, quality control, and post-translational processing, steps required for protein maturation. Dysregulation of these systems could represent potential mechanisms for abnormalities of neurotransmitter associated proteins in schizophrenia. We hypothesized that expression of ER processing pathways is dysregulated in schizophrenia. We characterized protein and complex expression of essential components from protein folding, ER quality control (ERQC), and ER associated degradation (ERAD) processes in the dorsolateral prefrontal cortex of 12 matched pairs of elderly schizophrenia and comparison subjects. We found increased expression of proteins associated with recognizing and modifying misfolded proteins, including UDP-glucose/glycoprotein glucosyltransferase 2 (UGGT2), ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2), and synoviolin (SYVN1)/HRD1. As SYVN1/HRD1 is a component of the ubiquitin ligase HRD1-SEL1L complex that facilitates ERAD, we immunoprecipitated SEL1L and measured expression of other proteins in this complex. In schizophrenia, SYVN1/HRD1 and OS-9, ERAD promoters, have increased association with SEL1L, while XTP3-B, which can prevent ERAD of substrates, has decreased association. Abnormal expression of proteins associated with ERQC and ERAD suggests dysregulation in ER localized protein processing pathways in schizophrenia. Interestingly, the deficits we found are not in the protein processing machinery itself, but in proteins that recognize and target incompletely or misfolded proteins. These changes may reflect potential mechanisms of abnormal neurotransmitter associated protein expression previously observed in schizophrenia.

11C](R)-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live Disc1 locus-impaired mice

Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C](R)-Rolipram binding was measured by PET in LI (n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [11C](R)-Rolipram total distribution volumes (VT) were calculated and corrected for plasma-free fraction (fP) measured in a separate group of LI (n = 6) and WT (n = 7) mice. PDE4 enzyme activity was measured using in vitro samples of cerebral cortices from groups of LI (n = 4), heterozygote (n = 4), and WT (n = 4) mice. Disc1 LI mice showed a 41% increase in VT (18 ± 6 vs. 13±4 mL/cm3, P = 0.04) compared to WT mice. VT/fP showed a 73% significant increase (90 ± 31 vs. 52 ± 15 mL/cm3, P = 0.004) in Disc1 LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences (p < 0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [11C](R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4–DISC1 interaction.

Commentary: Physical Functional Capacity and C-Reactive Protein in Schizophrenia.

Commentary: Physical Functional Capacity and C-Reactive Protein in Schizophrenia.

Associations between SNPs and immune-related circulating proteins in schizophrenia

Genome-wide association studies (GWAS) and proteomic studies have provided convincing evidence implicating alterations in immune/inflammatory processes in schizophrenia. However, despite the convergence of evidence, direct links between the genetic and proteomic findings are still lacking for schizophrenia. We investigated associations between single nucleotide polymorphisms (SNPs) from the custom-made PsychArray and the expression levels of 190 multiplex immunoassay profiled serum proteins in 149 schizophrenia patients and 198 matched controls. We identified associations between 81 SNPs and 29 proteins, primarily involved in immune/inflammation responses. Significant SNPxDiagnosis interactions were identified for eight serum proteins including Factor-VII[rs555212], Alpha-1-Antitrypsin[rs11846959], Interferon-Gamma Induced Protein 10[rs4256246] and von-Willebrand-Factor[rs12829220] in the control group; Chromogranin-A[rs9658644], Cystatin-C[rs2424577] and Vitamin K-Dependent Protein S[rs6123] in the schizophrenia group; Interleukin-6 receptor[rs7553796] in both the control and schizophrenia groups. These results suggested that the effect of these SNPs on expression of the respective proteins varies with diagnosis. The combination of patient-specific genetic information with blood biomarker data opens a novel approach to investigate disease mechanisms in schizophrenia and other psychiatric disorders. Our findings not only suggest that blood protein expression is influenced by polymorphisms in the corresponding gene, but also that the effect of certain SNPs on expression of proteins can vary with diagnosis.